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Lipid droplets (LDs) are organelles composed of a hydrophobic core (mostly triacylglycerols and steryl esters) delineated by a lipid monolayer and found throughout the tree of life. LDs were seen for a long time as simple energy storage organelles but recent works highlighted their versatile roles in several fundamental cellular processes, particularly during stress response. LDs biogenesis occurs in the ER and their number and size can be dynamically regulated depending on their function, e.g. during development or stress. Understanding their biogenesis and degradation mechanisms is thus essential to better apprehend their roles. LDs degradation can occur in the cytosol by lipolysis or after their internalization into lytic compartments (e.g. vacuoles or lysosomes) using diverse mechanisms that depend on the considered organism, tissue, developmental stage or environmental condition. In this review, we summarize our current knowledge on the different LDs degradation pathways in several main phyla of model organisms, unicellular or pluricellular, photosynthetic or not (budding yeast, mammals, land plants and microalgae). We highlight the conservation of the main degradation pathways throughout evolution, but also the differences between organisms, or inside an organism between different organs. Finally, we discuss how this comparison can help to shed light on relationships between LDs degradation pathways and LDs functions. • LD degradation occurs through two main pathways: lipolysis and lipophagy. • Key core components and initial degradation steps appear conserved. • Lipolysis regulation depends on the organism/tissue and conditions that trigger it. • Lipophagy pathways greatly differ among organisms. • Degradation mechanisms of LD condition the fate of LD components. [ABSTRACT FROM AUTHOR]

Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and associated with drug resistance in lung adenocarcinoma (LUAD). It's found that aldehyde dehydrogenase 2 (ALDH2), which is highly mutated in East Asian populations, is correlated with response to chemotherapy in LUAD patients. The rs671 variant knock-in, downregulation, and pharmacological inhibition of ALDH2 render LUAD cells more vulnerable to ferroptosis inducers and platinum-based chemotherapy. ALDH2 inhibits ferroptosis through the detoxification of 4-hydroxynonenal and malondialdehyde, the product of lipid peroxidation, as well as the production of NADH at the same time. Besides, ALDH2 deficiency leads to elevated intracellular pH (pHi), thus inhibiting the ERK/CREB1/GPX4 axis. Interestingly, ALDH2 is also regulated by CREB1, and the ALDH2 enzyme activity was decreased with elevated pHi. What's more, the elevated pHi caused by impaired ALDH2 activity promotes the biosynthesis of lipid droplets to counteract ferroptosis. At last, the effect of ALDH2 on ferroptosis and chemosensitivity is confirmed in patient-derived organoids and xenograft models. Collectively, this study demonstrates that ALDH2 deficiency confers sensitivity to platinum through ferroptosis in LUAD, and targeting ALDH2 is a promising new strategy to enhance the sensitivity of platinum-based chemotherapy for the treatment of LUAD patients. [Display omitted] • ALDH2 rs671 polymorphism is common in the Asian population. • ALDH2 deficiency renders lung adenocarcinoma (LUAD) more vulnerable to platinum via ferroptosis. • ALDH2 counteracts ferroptosis in a pH-dependent manner. • ALDH2 is a promising target for overcoming chemoresistance in LUAD patients. [ABSTRACT FROM AUTHOR]

Lipids have key functions in the assembly of cell structures, serve as an important energy source, and are precursors for signaling molecules. Ubiquitination is one of the most common post-translational modifications in eukaryotes and is essential for cellular and tissue homeostasis. Ubiquitination is central in regulating lipid metabolism by controlling the turnover of proteins and lipids involved in lipid metabolism. Dysregulation of ubiquitination contributes to lipid abnormalities in divergent disorders, and targeting the ubiquitin-proteasome system serves as an interesting therapeutic approach. Lipids are essential molecules that play key roles in cell physiology by serving as structural components, for storage of energy, and in signal transduction. Hence, efficient regulation and maintenance of lipid homeostasis are crucial for normal cellular and tissue function. In the past decade, increasing research has shown the importance of ubiquitination in regulating the stability of key players in different aspects of lipid metabolism. This review describes recent insights into the regulation of lipid metabolism by ubiquitin signaling, discusses how ubiquitination can be targeted in diseases characterized by lipid dysregulation, and identifies areas that require further research. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (APOE) mediates multiple aspects of brain lipid homeostasis in both physiological and pathological contexts. Evidence points to defects in metabolism, intracellular trafficking, and innate immune pathways, particularly in glial cells, underlying the pathogenic effects of the APOE4 variant in Alzheimer's disease. Understanding how E4 predisposes individuals to disease requires a deeper mechanistic understanding of the trafficking mechanisms of APOE within and between cells in the brain. Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes. [ABSTRACT FROM AUTHOR]

The liver plays a crucial role in lipid metabolism and metabolic homeostasis. Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease worldwide and currently has no specific treatments. Lifestyle modifications such as weight loss, exercise, and dietary changes are recommended to reduce the risk factors associated with the disease. Oxidized cholesterol products, some phospholipids and diacylglycerols can activate inflammatory pathways and contribute to the progression to Non-Alcoholic Steatohepatitis. Monitoring the whole plasma and liver lipidome may provide insights into the onset, development, and prevention of inflammatory-related diseases. As Lipid Droplets (LDs) represent augmented lipid reservoirs in NAFLD, new developments are being made on different therapies focused on LD associated proteins modulation (seipin, PLIN-2), as well as LD lipophagy mechanisms. The information covered in this publication provides an overview of the available research on lipid biomarkers linked to NAFLD and can be used to guide the development of future pharmacological therapies. • Plasma lipidome research emerges as a tool for understanding metabolic disorders. • Protein targets like seipin offers potential in NAFLD drug development. • Phosphatidylcholine & arachidonic acid metabolism may impact NAFLD pathogenesis. • Oxylipin profiling provides promising non-invasive diagnostic tools for NAFLD. [ABSTRACT FROM AUTHOR]

Organelles not only constitute the basic structure of the cell but also are important in maintaining the normal physiological activities of the cell. With the development of biomimetic nanoscience, researchers have developed technologies to use organelles as drug carriers for disease treatment. Compared with traditional drug carriers, organelle drug carriers have the advantages of good biocompatibility, high drug loading efficiency, and modifiability, and the surface biomarkers of organelles can also participate in intracellular signal transduction to enhance intracellular and intercellular communication, and assist in enhancing the therapeutic effect of drugs. Among different types of organelles, extracellular vesicles, lipid droplets, lysosomes, and mitochondria have been used as drug carriers. This review briefly reviews the biogenesis, isolation methods, and drug-loading methods of four types of organelles, and systematically summarizes the research progress in using organelles as drug-delivery systems for disease treatment. Finally, the challenges faced by organelle-based drug delivery systems are discussed. Although the organelle-based drug delivery systems still face challenges before they can achieve clinical translation, they offer a new direction and vision for the development of next-generation drug carriers. [Display omitted] • Described the isolation and drug-loading methods of four types of organelle carriers. • Organelle carriers are functional, biocompatible and modifiable. • Summarized the application of drug-loading organelles in different diseases. • Emphasized the challenges and future development of organelle drug delivery systems. [ABSTRACT FROM AUTHOR]

Present study investigated anti-obesity potential of Withania somnifera (L.) Dunal leaf extract (WSLE). Phytochemical characterization of WSLE was performed by UPLC/MS-QToF and HPLC-based analysis. WSLE was assessed for its effect on lipid metabolism and mitochondrial biogenesis in vitro using differentiated 3T3-L1 adipocytes. WSLE was found to contain 59 phytometabolites with a total of 10.601 μg withanolides per mg of extract. WSLE (30 μg/ml) treatment decreased basal levels of intracellular lipids and triglycerides to 13.85 % and 41.58 %, respectively. WSLE downregulated the expression of PPARγ, C/EBPα, C/EBPβ, and their target genes responsible for lipogenesis dose-dependently. An upregulation in expression of lipolytic (ATGL and HSL), thermogenic (PGC1α, UCP1, and PRDM16), and glucose transporter (GLUT4) genes was also observed. Furthermore, WSLE treatment increased glucose uptake by 1.5-fold. These beneficial effects of WSLE were abolished in presence of AMPK, p38MAPK, and ERK inhibitors. These observations were then validated in vivo using Caenorhabditis elegans as a model organism. Intriguingly, WSLE diminished fat accumulation in wild-type N2 worms as evident from reduced Oil-red-O staining and reduction in GFP expression of fat-5, 6, and 7 in transgenic strains. Overall, these results highlight anti-obesity potential of WSLE exerting its effects via alterations in AMPK/p38MAPK/ERK axis. • WSLE treatment decreased intracellular lipid accumulation in adipocytes. • WSLE mediates its anti-obesity effects via AMPK/p38MAPK/ERK signaling axis. • WSLE treatment reduced the expression of fat-5, fat-6, and fat-7 in C. elegans. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are ubiquitous intracellular organelles present in various cell types, ranging from adipocytes to cancer cells. Despite their involvement in numerous diseases, current methodologies for monitoring LD dynamics rely primarily on static imaging with a limited selection of fluorescent dyes. In this study, we introduce two novel BODIPY-derived fluorophores designed to facilitate real-time monitoring of LD dynamics. By incorporating triphenylamino (TPA) moieties into the BODIPY core both asymmetrically and symmetrically, we modulated the fluorescence response to the green (GFP) and deep-red (Cy5) confocal channels, respectively, thus allowing dual-channel fluorescence capability for high-resolution, dynamic imaging of LDs within live cells, providing new insights into their behavior. [Display omitted] [ABSTRACT FROM AUTHOR]

During the process of ferroptosis, the generation of toxic lipid peroxides triggers severe inflammatory responses. Despite sulfur dioxide (SO 2) being recognized as an important signal molecule and antioxidant, its specific physiological mechanism in ferroptosis remains unclear. Here, we developed a novel probe, SP-TB , tailored for detecting SO 2 within lipid droplets (LDs). SP-TB features a triphenylamine moiety for LD targeting, coupled with a spiropyran serving as both the SO 2 reaction site and a light-responsive switch. Under normal conditions, SP-TB exhibits yellow fluorescence at 570 nm with its SO 2 reaction site closed. Upon UV light activation, the spiropyran moiety undergoes isomerization to the merocyanine form (MC-TB), resulting in red fluorescence emission at 634 nm. During this photoisomerization, the exposed C C-C N+ fragment enables specific Michael addition reactions with SO 2 , quenching the red fluorescence of MC - TB and enhancing yellow fluorescence. The probe exhibits stable photoreversibility and excellent LDs targeting, along with remarkable SO 2 selectivity with a low detection limit of 3.5 μM. Notably, the controllability of the SO 2 reaction site minimizes false positives. This probe was successfully used to monitor the changes of SO 2 concentrations in LDs during ferroptosis. [Display omitted] • A novel light-controlled fluorescent probe (SP-TB) for detecting SO 2 in LDs. • Remarkable selectivity and sensitivity for SO 2 with a low detection limit of 3.5 μM. • Successful monitoring of dynamic SO 2 changes in LDs during ferroptosis. • In vivo imaging of ferroptosis-induced SO 2 fluctuations in a zebrafish model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Developed polarity-sensitive fluorescent probe TPE-BD for targeting lipid droplets (LDs) in cells. • Explored optical properties, TPE-BD was sensitive and selective to polarity. • TPE-BD shows low cytotoxicity, targeting ability, and potential for real-time LD and ferroptosis monitoring. Ferroptosis can regulate cell death by accumulating lipid peroxides, affecting the structure and polarity of lipid droplets (LDs), but clear evidence is still lacking. Fluorescence imaging is the most powerful technique for studying LDs' function. However, developing AIE fluorescent probes with high selectivity and sensitivity for targeting LDs remains challenging. In this study, we rationally designed an AIEgen, as a novel fluorescent probe TPE-BD , by constructing a push-pull electron structure. The probe has benzo[b]thiophene-3(2H)-one 1,1-dioxide as the electron acceptor, tetraphenylethylene (AIE skeleton) as the electron donor, and thiophene as the bridging group. The optical performance of probe TPE-BD indicated that the UV–visible absorption spectrum of the probe was minimally affected by solvent polarity (except for glycerol and PBS solvents), but the fluorescence of probe is very sensitive to changes in polarity, achieving the goal of polarity detection in LDs. CCK-8 assay and cell imaging experiments demonstrated that probe TPE-BD exhibited good cell compatibility and effectively targeted LDs, enabling the monitoring of LDs' polarity and quantity during ferroptosis. [ABSTRACT FROM AUTHOR]

Understanding the diffusion process of hydrophobic molecules through natural phospholipid (half-)membranes is of great importance, as it occurs within organisms and therefore, offers potential applications in encapsulation in natural carriers. One illustrative case involves oleosomes, lipid droplets found in eukaryotic cells, which possess a phospholipid-protein monolayer facilitating the incorporation of lipophilic compounds into their inner core. Our approach entailed the development of a mathematical model to elucidate the diffusion of a lipophilic molecule, specifically curcumin, into oleosomes. In this model, oleosomes were represented as multilayer spheres with position-dependent diffusion and partition coefficients. We derived the model parameters through experimental techniques and stablished empirical equations. The model showed that 80% of curcumin reached the oil core while 20% stayed within the membrane (phospholipid heads and tails). Beyond its application to oleosomes and curcumin, the model presented herein holds broad application for describing the encapsulation of various lipophilic molecules into carriers featuring phospholipid (half-)membranes. [Display omitted] • A dynamic 1D model is used to study the mass transfer of curcumin in oleosomes. • The model is experimentally validated at equilibrium. • 80% of curcumin penetrated the oleosome core, while 20% at the interface. • The oil core contained the highest encapsulated mass. [ABSTRACT FROM AUTHOR]

Rabies, induced by rabies virus (RABV), still threaten global health all over the world, and no effective therapy is available for rabies currently. Recently, a series of natural plant components have been found to inhibit virus production. In this study, Z-Ligustilide, a natural component of Ligusticum chuanxiong Hort , was found to inhibit RABV replication. Initially, the concentration of cytotoxicity 50 % (CC 50) of Z-Ligustilide in N2a and BSR cells were 429.9 μM and 335.5 μM, respectively, which both significantly restrict RABV production in a concentration-dependent manner. Moreover, Z-Ligustilide was found to mainly inhibit the replication stage of RABV. Specifically, Z-Ligustilide can suppress lipid droplet (LD) formation via directly inhibiting diacylglycerol acyltransferase 1/2 (DGAT1/2) expression, which can further promote cellular lipid peroxidation, Fe2+ concentration, reactive oxygen species (ROS), and induce ferroptosis ultimately. Furthermore, Z-Ligustilide was demonstrated to increase ferroptosis via Acyl-CoA synthetase long-chain family member 4 (ACSL4)- Lysophosphatidylcholine Acyltransferase 3 (LPCAT3)- Cytochrome P450 Oxidoreductase (POR) pathway. Above all, this study explored the antiviral function of Z-Ligustilide, which provides a novel insight for developing anti-RABV drugs. • Z-Ligustilide, a natural component of Ligusticum chuanxiong Hort, inhibits RABV replication in vitro and vivo. • Z-Ligustilide suppresses lipid droplets via inhibiting DGAT expression to restrict RABV infection • Z-Ligustilide induces ferroptosis via ACSL4-LPCAT3-POR axis to inhibit RABV replication. [ABSTRACT FROM AUTHOR]

• Four compounds XOT1 - XOT4 with different terminal groups were synthesized using triphenylamine and coumarin as the main substituents. • The fluorescence intensity of XOT1 - XOT4 exhibited a good linear correlation with polarity. • Among them, XOT3 with ester group can effectively monitor changes in LDs polarity during apoptosis and ferroptosis process. • XOT3 could be effectively utilized for visualizing intracellular LDs without requiring any washing steps. • XOT3 was capable of effectively visualizing LDs in tissues and organs in mouse models of NAFLD. Aberrant alterations in the polarity of lipid droplets (LDs) are closely linked to disorders of lipid metabolism, which can result in LDs dysfunction and the onset of various diseases, including non-alcoholic fatty liver disease (NAFLD) and specific types of cancer. Therefore, it is imperative to comprehensively comprehend and accurately diagnose associated diseases by monitoring changes in LDs polarity in real time. In this paper, we designed and synthesized four novel fluorescent probes XOT1 - XOT4 by using coumarin as a polarity-sensitive group and incorporate various triphenylamine derivatives as electron-donating groups, enabling specific targeting of LDs. All four probes possess high sensitivity towards minute polarity changes. Among them, XOT3 exhibited excellent photophysical properties and demonstrated a linear fluorescence change (R 2 = 0.98596) within the polarity range of Δ f = 0.023496 ∼ 0.047464. Moreover, probe XOT3 could be effectively utilized for visualizing intracellular LDs by precisely targeting them without requiring any washing steps. Importantly, probe XOT3 has been successfully utilized to monitor alterations in the polarity of LDs during apoptosis and ferroptosis as well as the quantity, size, and fluorescence intensity of LDs stimulated by oleic acid. Furthermore, probe XOT3 was capable of effectively visualizing LDs in tissues and organs in mouse models of non-alcoholic fatty liver disease (NAFLD), which provides a powerful tool for the early diagnosis of NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

Unraveling the inherent association between diseases and hypochlorous acid (HOCl), within the microenvironments of lipid droplets (LD) remains a formidable task due to the scarcity of research on multiple disease models. Intracellular HOCl and microenvironments (such as viscosity and polarity), are crucial in upholding redox balance, orchestrating diffusion, transportation and signal transduction within living cells. Nevertheless, the simultaneous visualization of HOCl alongside viscosity and polarity within the milieu of ferroptosis, inflammation, and neoplasia remains unachieved due to the absence of appropriate analytical tools. In response to this pressing need, we have developed an innovative, multifunctional near infrared (NIR) fluorescent probe, termed NCN , capable of simultaneously monitoring HOCl, viscosity, and polarity within lipid droplets. NCN is characterized by its heightened sensitivity to increased viscosity and decreased polarity, which allows it to target LDs with high specificity. Furthermore, the combined application of HOCl, viscosity, and polarity as diagnostic markers for cancer has been triumphantly demonstrated, encompassing cellular and tissue strata as well as in vivo tumor-bearing mouse models. Therefore, our probe offers a reliable means for understanding LD microenvironments and proposes a promising approach for the diagnostic evaluation of diseases. [Display omitted] • Three novel fluorescent probes were judiciously designed and proposed. • NCN can simultaneously monitor viscosity, polarity, and HOCl in zebrafish. • NCN enables the multifunctional detection of NAFLD, cancer, and inflammation models. [ABSTRACT FROM AUTHOR]

[Display omitted] • TST has excellent NIR emission properties and a large Stokes shift. • TST can be used to target LDs by a wash-free procedure. • TST enables real-time monitoring of the spatial properties of LDs. • TST can be used to respond to changes in polarity under different cellular conditions. • TST has the potential to diagnose NAFLD. Nowadays, it has been proven that lipid droplets (LDs) not only maintain the fundamental cellular functions, but also play an essential role in the pathogenesis of numerous diseases. Non-alcoholic fatty liver disease (NAFLD) is among these diseases. In this work, we designed two polarity sensitive fluorescent probes TST and TSO with D-π-A-D structure by introducing different electron acceptor groups according to the low polarity of LDs. The experimental discovered that probe TST exhibited the characteristics of near-infrared emission, high selectivity towards polarity, large Stokes shift, rapid targeting ability of LDs, and robust wash-free biological imaging capability. Confocal images illustrated that probe TST has been successfully applied in monitoring LDs polarity during ferroptosis, as well as visualizing changes in LDs polarity at both tissue and organ levels in fatty liver conditions. With these exceptional properties, probe TST was anticipated to make further contributions to the field of LDs research. [ABSTRACT FROM AUTHOR]

[Display omitted] • Long-term arsenic exposure leads to weight loss and lipid droplet reduction. • The Gpat gene may be involved in the reduction of lipid droplets. • Arsenic exposure disrupts gut homeostasis, indirectly impairing liver function. • Long-term arsenic exposure primarily disturbs liver lipid metabolism. Arsenic (As) is a widespread global pollutant, and there is significant controversy surrounding its complex relationship with obesity, primarily focused on short-term exposure. Recognizing the prolonged nature of dietary arsenic exposure, this study involved feeding mice with arsenic-contained food for 14 months. The results showed that mice exposed to arsenic developed a non-alcoholic fatty liver condition, characterized by a light-yellow hue on the liver surface and various pathological alterations in the liver cells, including enlarged nuclei, cellular necrosis, inflammatory infiltration, dysfunctional mitochondria, and endoplasmic reticulum disorganization. There were also disruptions in biochemistry indices, with a significant increase in total cholesterol (TC) level and a decrease in high-density lipoprotein (HDL) level. However, some contradictory observations occurred, such as a significant decrease in body weight, triglyceride (TG) level, and the numbers of lipid droplets. Several genes related to lipid metabolism were tested, and a model was used to explain these discrepancies. Besides, examinations of the colon revealed compromised intestinal barrier function and signs of inflammation. Fecal 16S rRNA sequencing and pseudo-targeted metabolomics revealed disruptions in internal homeostasis, such as modules, nodes, connections, and lipid-related KEGG pathways. Fecal targeted metabolomics analyses of short-chain fatty acids (SCFAs) and bile acids (BAs) demonstrated a significant upregulation in three primary bile acids (CA, CDCA, TCDCA), four secondary bile acids (TUDCA, DCA, LCA, GUDCA), and total SCFAs level. Oxidative stress and inflammation were also evident. Additionally, based on correlation analysis and mediation analysis, it was assumed that changes in the microbiota (e.g., Dubosiella) can impact the liver metabolites (e.g., TGs) through alterations in fecal metabolites (e.g., LPCs). These findings provide a theoretical reference for the long-term effect of arsenic exposure on liver lipid metabolism. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) are a series of disorders characterized by the progressive loss of specific neurons, leading to cognitive and locomotor impairment. NDDs affect millions of patients worldwide but lack effective treatments. Dysregulation of lipids, particularly the accumulation of lipid droplets (LDs), is strongly implicated in the pathogenesis of NDDs. How LDs contribute to the occurrence and development of NDDs, and their potential as therapeutic targets remain to be addressed. In present review, we first introduce the processes of LDs formation, transportation and degradation. We then highlight how the accumulation of LDs contributes to the pathogenesis of NDDs in a cell type-specific manner. Moreover, we discuss currently available methods for detecting LDs and elaborate on LDs-based therapeutic strategies for NDDs. Lastly, we identify gaps that need to be filled to better leverage LD-based theranostics in NDDs and other diseases. We hope this review could shed light on the role of LDs in NDDs and facilitate the development of novel therapeutic strategies for NDDs. • LDs are the organelles in cells playing important physiological roles. • LDsaccumulationis observed in the brain of animalsand patients with NDDs. • LDs contribute pathogenesis of NDDs by impairing function of neuron, microglia, astrocyte and other types of cells in brain. • LDs based detection and intervention hold great potential for effective treatment of NDDs. [ABSTRACT FROM AUTHOR]

[Display omitted] • All four probes exhibited high sensitivity and specificity for polarity changes. • Probes CNL2 and CNL4 exhibited a long emission wavelength (>650 nm). • CNL2 and CNL4 possess excellent wash-free imaging capabilities and superior LDs targeting abilities. • CNL4 effectively monitors changes in LDs polarity under conditions of ferroptosis and oxidative stress. • CNL4 can be capable of monitoring the process of lipophagy and the early diagnosis of fatty liver at the tissue level. Lipid droplets (LDs), as primary cellular energy storage organelles, play essential roles not only in energy conservation but also in inflammatory responses, apoptosis, and the progression of diseases such as non-alcoholic fatty liver disease (NAFLD). Studies indicate that alterations in the polarity of LDs are closely linked to pathological factors like oxidative stress, ferroptosis, and lipophagy. Therefore, developing biological probes for precisely monitoring LDs polarity is crucial for understanding these biological phenomena and devising new therapeutic strategies. In this context, we synthesized four fluorescent probes (CNL1 - CNL4) to precisely monitor the polarity of LDs using triphenylamine and carbazole derivatives as electron donors and isophorone and benzopyranonitrile units as electron acceptors, employing intramolecular charge transfer (ICT) mechanism. Our findings demonstrated that all four probes exhibited high sensitivity and specificity for polarity changes. Probes CNL2 and CNL4 were sensitive to polarity, and their maximum fluorescence intensity and maximum emission wavelength demonstrated a good linear relationship with polarity parameters within a certain range. Biological experiments demonstrated that both CNL2 and CNL4 possess excellent wash-free imaging capabilities and superior LDs targeting abilities but also enable dynamic monitoring of LDs and respond well to changes in LDs polarity under varying concentrations of oleic acid stimulation. Due to its longer emission wavelength (>650 nm), boasting excellent photostability, and featuring a larger Stokes shift (≈168 nm in acetonitrile), probe CNL4 was selected for further studies. Furthermore, probe CNL4 effectively monitors changes in LDs polarity under conditions of ferroptosis and oxidative stress. It has shown potential in the diagnosis of NAFLD tissue and during the process of lipophagy, highlighting its value in disease diagnostics and biological research. These findings not only deepen our understanding of the mechanisms underlying NAFLD progression but also provide new tools for diagnosing and treating related diseases. [ABSTRACT FROM AUTHOR]

Leydig cells are important component of testis cells, which can synthesize testosterone with free cholesterol derived from lipid droplets (LDs). It is well known that melatonin could regulate synthesis of testosterone. However, it is still unclear whether melatonin participates in the synthesis of testosterone by regulating the lipolysis of LDs in Leydig cells. The purpose of this study was to elucidate the effect of melatonin on synthesis of testosterone in roosters Leydig cells by regulating lipolysis of LDs. The results showed that melatonin decreased synthesis of testosterone and intracellular free cholesterol in roosters Leydig cells. Exogenous addition of 22-OH-Cholesterol counteracted the inhibitory effect of melatonin on synthesis of testosterone. Furthermore, melatonin increased the LDs content and expression of perilipin 1 (PLIN1), and decreased expression of hormone-sensitive lipase (HSL) and triacylglycerol hydrolase (ATGL) in roosters Leydig cells. In addition, silencing PLIN1 reversed the inhibitory effect of melatonin on synthesis of testosterone in roosters Leydig cells by increasing free cholesterol content and expression of HSL and ATGL, and decreasing the lipid droplet content. Activation of cAMP/PKA pathway by using the pathway activators Forskolin and 8-Bromo-cAMP attenuated the inhibitory effect of melatonin on synthesis of testosterone accompanied by increasing level of free cholesterol content and expression of HSL and ATGL, and decreasing level of lipid droplet content and expression of PLIN1 in roosters Leydig cells. These results suggested that melatonin could inhibit the synthesis of testosterone in roosters Leydig cells by reducing the content of intracellular free cholesterol in which expression of PLIN1 and cAMP/PKA pathway were inhibited to reduce the lipolysis of LDs. • Melatonin inhibits the synthesis of testosterone in roosters Leydig cells by regulating lipid droplets (LDs). • Melatonin inhibits lipolysis of LDs by promoting the expression of PLIN1. • Melatonin reduces free cholesterol content in roosters Leydig cells by inhibiting lipolysis of LDs. • Melatonin inhibits lipolysis of LDs and testosterone synthesis in roosters Leydig cells via cAMP/PKA signaling pathway. [ABSTRACT FROM AUTHOR]

The accumulation of lipid droplets in hepatocytes is a key feature of drug-induced liver injury (DILI) and can be induced by a subset of hepatotoxic compounds. In the present study, we optimized and evaluated an in vitro technique based on the fluorescent dye Nile Red, further named Nile Red assay to quantify lipid droplets induced by the exposure to chemicals. The Nile Red assay and a cytotoxicity test (CTB assay) were then performed on cells exposed concentration-dependently to 60 different compounds. Of these, 31 were known to induce hepatotoxicity in humans, and 13 were reported to also cause steatosis. In order to compare in vivo relevant blood concentrations, pharmacokinetic models were established for all compounds to simulate the maximal blood concentrations (C max) at therapeutic doses. The results showed that several hepatotoxic compounds induced an increase in lipid droplets at sub-cytotoxic concentrations. To compare how well (1) the cytotoxicity test alone, (2) the Nile Red assay alone, and (3) the combination of the cytotoxicity test and the Nile Red assay (based on the lower EC 10 of both assays) allow the differentiation between hepatotoxic and non-hepatotoxic compounds, a previously established performance metric, the Toxicity Separation Index (TSI) was calculated. In addition, the Toxicity Estimation Index (TEI) was calculated to determine how well blood concentrations that cause an increased DILI risk can be estimated for hepatotoxic compounds. Our findings indicate that the combination of both assays improved the TSI and TEI compared to each assay alone. In conclusion, the study demonstrates that inclusion of the Nile Red assay into in vitro test batteries may improve the prediction of DILI compounds. [Display omitted] • Drug-induced lipid droplet accumulation can be quantified by the Nile Red assay in HepG2 cells. • The Nile Red assay improves the separation of hepatotoxic and non-hepatotoxic substances. • The improved separation is evidenced by the Toxicity Separation Index (TSI). • For several steatosis inducing compounds the Nile Red assay resulted in lower effective concentrations than a viability test. [ABSTRACT FROM AUTHOR]

[Display omitted] • The simultaneous visualization of LDs and ER by all probes is highly significant for investigating organelle interactions. • All probes showed high sensitivity to polarity and could be used for quantitative detection of polarity. • Probe COB2 could monitor the dynamic behavior of LDs in living cells. • Probe COB2 could be used to observe the changes in LDs and ER under different apoptosis patterns. • Probe COB2 was successfully applied to diagnosing the fatty liver tissues. Non-alcoholic fatty liver disease (NAFLD) becomes a world health issue due to its rising prevalence and lack of a definitive pathogeny. However, the excessive accumulation of fat droplets has been recognized as a crucial characteristic of NAFLD, accompanied with endoplasmic reticulum stress in its onset and progression as well. Therefore, real-time monitoring the dynamic of lipid droplets (LDs) and endoplasmic reticulum (ER) within cells is paramount. In this regard, four D-A-π-D structural fluorescent probes COB1 - COB4 were designed and synthesized wherein coumarin connected with carbazole acted as precursors while the side chains attached to carbazole groups are different. Here, probes COB1 - COB4 exhibited high sensitivity towards polarity, while COB2 was chosen for further study attributing to its excellent anti-interference property. Cell imaging demonstrated that COB2 could accurately target both LDs and ER at the same time and monitor the changes of the two organelles under different physiological conditions. Notably, probe COB2 also exhibited the ability to distinguish normal liver from fatty liver at the tissue level. The above results lay an experimental foundation for developing novel dual-targeted probes with potential for early diagnosis of non-alcoholic fatty liver. [ABSTRACT FROM AUTHOR]

Extracellular acidosis stemming from altered tumor metabolism promotes cancer progression by enabling tumor cell adaptation to the hostile microenvironment. In osteosarcoma, we have previously shown that acidosis increases tumor cell survival alongside substantial lipid droplet accumulation. In this study, we explored the role of lipid droplet formation in mitigating cellular stress induced by extracellular acidosis in osteosarcoma cells, thereby enhancing tumor survival during progression. Specifically, we examined how lipid droplets shield against reactive oxygen species induced by extracellular acidosis. We demonstrated that lipid droplet biogenesis is critical for acid-exposed tumor cell survival, as it starts shortly after acid exposure (24 h) and inversely correlates with ROS levels (DCFH-DA assay), lipid peroxidation (Bodipy assay), and the antioxidant response, as also revealed by NRF2 transcript. Additionally, extracellular metabolites, such as lactate, and interaction with mesenchymal stromal cells within the tumor microenvironment intensify lipid droplet build-up in osteosarcoma cells. Critically, upon targeting two key proteins implicated in LD formation - PLIN2 and DGAT1 - cell viability significantly declined while ROS production escalated. In summary, our findings underscore the vital reliance of acid-exposed tumor cells on lipid droplet formation to scavenge oxidative stress. We conclude that the rewiring of lipid metabolism driven by microenvironmental cues is of paramount importance for the survival of metabolically altered osteosarcoma cells in acidic condition. Overall, we suggest that targeting key members of lipid droplet biogenesis may eradicate more aggressive and resistant tumor cells, uncovering potential new treatment strategies for osteosarcoma. [Display omitted] • Lipid droplet formation mitigates cellular stress • Targeting proteins involved in lipid droplet formation leads to a decline in cell viability and increased ROS production • Lactate is a key metabolite in lipid droplet formation • Lipid droplet biogenesis is fuelled by tumor-associated stromal cells [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is one of the most common liver diseases. The crucial role of lipid droplets (LDs) and hydrogen peroxide (H 2 O 2), two important biomarkers in the pathophysiology of DILI, has spurred considerable efforts to accurately visualize H 2 O 2 and LDs for elucidating their functions in the progression of DILI. However, construction of a single fluorescent probe that is able to simultaneously image H 2 O 2 and LDs dynamics remains to be a challenging task. Therefore, it is of great demand to develop a novel fluorescent probe for tracking the LDs status and H 2 O 2 fluctuation in drug-induced liver injury. We developed an "AIE + ESIPT" fluorescent probe TPEHBT for dual-imaging of LDs and H 2 O 2 during DILI process. TPEHBT displayed greatly enhanced fluorescent response to H 2 O 2 by generating an excited state intramolecular proton transfer (ESIPT) fluorophore TPEHBT-OH with aggregation induced emission (AIE) properties. TPEHBT exhibits high selectivity, sensitivity (LOD = 4.73 nM) and large Stokes shift (320 nm) to H 2 O 2. Interestingly, TPEHBT can light up LDs with high specificity. The probe was favorably applied in the detection of endogenous and exogenous H 2 O 2 in living cells, and notably in the simultaneous real-time visualization of H 2 O 2 generation and LDs accumulation during DILI process. Moreover, TPEHBT was able to image H 2 O 2 generation in zebrafish animal model with APAP-induced liver injury. For the first time, probe TPEHBT was applied in the dual-imaging of H 2 O 2 fluctuation and LDs status in APAP-induced liver injury model in vitro and in vivo. The present findings strongly suggest that TPEHBT is a promising tool for monitoring H 2 O 2 and LDs dynamics in DILI progression. A novel activatable "AIE + ESIPT" fluorescent probe TPEHBT for dual-imaging of LDs and H 2 O 2 was synthesized. In the presence of H 2 O 2 , TPEHBT exhibited remarkable fluorescence enhancement, large Stokes shift, outstanding sensitivity and high selectivity. Colocalization experiment showed that TPEHBT possessed strong LDs-targeting ability with high PCC of 0.94. Remarkably, TPEHBT was not only capable of monitoring exogenous and endogenous H 2 O 2 in live cells, but also simultaneously tracking the accumulation of LDs and upregulation of H 2 O 2 levels during APAP-induced liver injury process. Furthermore, in vivo imaging experiment suggests that TPEHBT has been successfully used to monitor liver injury in zebrafish. [Display omitted] • A novel "AIE + ESIPT" fluorescent probe TPEHBT was synthesized. • TPEHBT exhibits high selectivity, sensitivity and large Stokes shift to H 2 O 2. • TPEHBT can light up LDs with high specificity. • TPEHBT was employed for imaging of endogenous and exogenous H 2 O 2 in living cells. • TPEHBT was applied in dual-imaging of H 2 O 2 and LDs in APAP-induced liver injury model. [ABSTRACT FROM AUTHOR]

Sertoli cells (SCs) are essential for appropriate spermatogenesis. From a metabolic standpoint, they catabolize glucose and provide germ cells with lactate, which is their main energy source. SCs also oxidize fatty acids (FAs), which are stored as triacylglycerides (TAGs) within lipid droplets (LDs), to fulfill their own energy requirements. On the other hand, it has been demonstrated that FSH regulates some of SCs functions, but little is known about its effect on lipid metabolism. In the present study, we aimed to analyze FSH-mediated regulation of (1) lipid storage in LDs and (2) the expression of genes involved in FAs activation and TAG synthesis and storage in SCs. SCs obtained from 20-day-old rats were cultured for different incubation periods with FSH (100 ng/ml). It was observed that FSH increased LD content and TAG levels in SCs. There were also increments in the expression of Plin1, Fabp5, Acsl1, Acsl4, Gpat3 , and Dgat1 , which suggests that these proteins may mediate the increase in TAGs and LDs elicited by FSH. Regarding the signaling involved in FSH actions, it was observed that dbcAMP increased LD, and H89, a PKA inhibitor, inhibited FSH stimulus. Also, dbcAMP increased P lin2, Fabp5, Acsl1, Acsl4, and Dgat1 mRNA levels, confirming a role of the cAMP/PKA pathway in the regulation of lipid storage in SCs. Altogether, these results suggest that FSH, via the cAMP/PKA pathway, regulates lipid storage in SCs ensuring the availability of substrates to satisfy their energy requirements. [Display omitted] • FSH increases Sertoli cell lipid droplets and TAG content. • FSH regulates the expression of genes involved in lipid metabolism. • The cAMP/PKA pathway mediates FSH effects on lipid droplet content. [ABSTRACT FROM AUTHOR]

Lipophagy as a form of autophagy, can degrade lipid droplets, thereby acting as a critical regulator of cellular lipid metabolism, helping maintain the intracellular lipid homeostasis. In this study, we developed LP-SCUN , a far-red fluorescent probe for pinpointing lipid droplets with high sensitivity to solvent polarity. This probe allows for in situ imaging of lipophagy, tracking how lipid droplets move from non-polar to polar environments within lysosomes, leading to noticeable changes in fluorescence signals. The triphenylamine and triethylene glycol monomethyl ether groups of LP-SCUN facilitated its selective binding toward lipid droplets. Significantly, lipophagy and subsequent formation of autolysosomes decreased the environmental polarity, leading to a significant decrease in red fluorescence intensity (λ ex = 500 nm and λ em = 643 nm). As such LP-SCUN was suitable for the in situ and real-time tracking of the cellular lipophagic processes. With this research we used LP-SCUN to elucidate the mechanism of lipid metabolism in liver cells of palmitate-induced hyperlipidemia cell models and high-fat diet-induced hyperlipidemia animal models. The results indicated that non-alcoholic fatty liver disease (NAFLD) can trigger an increase in cell lipophagy levels, while the inhibition of cell lipophagy can effectively alleviate the damage caused by NAFLD to cells and liver tissue in mice. • A lipid droplet anchoring polar-sensitive fluorescent probe was developed for the imaging of lipophagy. • Lipophagy was evaluated during non-alcoholic fatty liver disease. • Near-infrared emission and large Stokes shift of the probe enabled high-resolution in vivo imaging. [ABSTRACT FROM AUTHOR]

Abnormal lipid metabolism in glial cells is a key pathological feature of epilepsy. The identification of lipid droplets (LDs) is essential for investigating lipid metabolism, disease progression, and potential therapeutic interventions. Two-photon imaging technology enables real-time visualization of the spatial distribution and temporal dynamics of LDs in epilepsy models. In this study, we developed a novel two-photon excited dual-responsive near-infrared fluorescent probe, CabA , based on viscosity and polarity, to monitor dynamic changes in LDs. The fluorescence of CabA at 670 nm exhibits a significant increase in response to low polarity and high viscosity due to the twisted intramolecular charge transfer and intramolecular charge transfer mechanisms. The LDs-targeting capability of CabA at the cellular level and the process of LDs generation between neurons and astrocytes during the pathological advancement of epilepsy have been validated. In situ synchronous imaging experiments in epileptic and normal mice using CabA revealed abnormal LDs accumulation in the brain during seizures. Two-photon fluorescence imaging further demonstrated LDs accumulation in the brains of epileptic mice at a penetration depth of 100 μm. This study offers a valuable tool for enhancing the understanding of LDs in physiological and pathological processes, potentially aiding in the early diagnosis of epilepsy. [ABSTRACT FROM AUTHOR]

Ferrous ions (Fe2⁺) accumulation and abnormal alterations in lipid droplets (LDs) are closely associated with ferroptosis. In the liver, excessive iron accumulation promotes oxidative stress and exacerbates lipid droplet accumulation, while the disruption of iron homeostasis may also affect the formation and size of lipid droplets, their increased number and size can exacerbate the severity of disease under fatty liver conditions. The leads to hepatocyte damage, further triggering liver inflammation, fibrosis, and ultimately resulting in cirrhosis and hepatocellular carcinoma. Therefore, real-time monitoring of iron ion and lipid droplet changes is crucial for assessing the severity of liver disease, disease progression, and understanding the mechanisms of ferroptosis. We have developed a fluorescent probe, NRFep, for real-time monitoring of iron ion fluctuations and visualization of lipid droplet changes in ferroptosis and liver disease models. NRFep is specific and sensitive to iron ions and exhibits excellent stability in both cells and animal models. In addition, NRFep can be used to monitor changes in iron ions and lipid droplets in mouse liver injury and fatty liver models. Through fluorescence lifetime imaging technology, NRFep can also study the dynamic changes of intracellular iron ion content. NRFep provides a powerful tool for studying ferroptosis and related diseases, and its unique dual-monitoring function opens up new possibilities for developing new diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

The interaction between lipid droplets and mitochondria plays a pivotal role in biological processes including cellular stress, metabolic homeostasis, cellular autophagy and apoptosis. Deciphering the complex interplay between lipid droplets and mitochondria is essential for gaining insights into the fundamental workings of the cell and can have broad implications for the development of therapeutic strategies for various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. In this study, we develop a pH and viscosity-responsive near-infrared (NIR) fluorescent probe PTOH to investigate the interaction between lipid droplets and mitochondria. This probe demonstrates a significant enhancement in fluorescence intensity at 470 nm when the pH increases, while under acidic conditions, its fluorescence intensity at 730 nm intensifies by a factor of 35 with rising system viscosity. Cell imaging experiments revealed that PTOH can effectively discriminate between normal and cancerous cells, as well as detect intracellular pH and viscosity alterations induced by drugs. Additionally, PTOH is utilized to visualize the interaction between lipid droplets and mitochondria and to differentiate between cellular autophagy and apoptosis phenomena, providing a valuable tool for elucidating the mechanisms underlying lipid droplet-mitochondria interactions and their associated diseases. Autophagy can affect the apoptotic threshold of tumor cells and may influence tumor cell survival by regulating apoptosis-related genes. Therefore, we synthesized a near-infrared fluorescent probe, PTOH , with the ability to detect pH and viscosity to distinguish between normal cells and cancer cells, and between autophagy and apoptosis. [Display omitted] • Benzoindole salts partially positively charged of PTOH can target mitochondria. • PTOH can distinguish normal cells from cancer cells by monitoring changes in intracellular pH. • PTOH distinguishes between apoptosis and cellular autophagy by dual-color recognition. • Mitochondrial dysfunction occurs in autophagy, leading to an increase of number of LDs. • During apoptosis, mitochondria provide the capacity needed for cellular activity. [ABSTRACT FROM AUTHOR]

In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs' lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes. [ABSTRACT FROM AUTHOR]

Astrocytes, the predominant glial cells in the central nervous system (CNS), play diverse roles including metabolic support for neurons, provision of neurotrophic factors, facilitation of synaptic neurotransmitter uptake, regulation of ion balance, and involvement in synaptic formation. The accumulation of lipids has been noted in various neurological conditions, yet the response of astrocytes to lipid-rich environments remains unclear. In this study, primary astrocytes isolated from the neonatal rat cortex were exposed to a lipid mixture (LM) comprising cholesterol and various fatty acids to explore their reaction. Our results showed that astrocyte viability remained unchanged following 24 h of 5% or 10% LM treatment. However, exposure to LM for 96 h resulted in reduced cell viability. In addition, LM treatment led to the accumulation of lipid droplets (LDs) in astrocytes, with LD size increasing over prolonged exposure periods. Following 24 h of LM treatment and then 48 h in fresh medium, a significant reduction in intracellular LD size was observed in cultures treated with 5% LM, while no change occurred in cultures exposed to 10% LM. Yet, exposure to 10% LM for 24 h significantly increased the expression of the cholesterol efflux regulatory protein/ATP-binding cassette transporter (ABCA1) gene, responsible for intracellular cholesterol efflux, resulting in reduced cholesterol content within astrocytes. Moreover, LM exposure led to decreased mitochondrial membrane potential (MMP) and increased levels of mature apoptosis-inducing factor (AIF). The smaller LDs were observed to co-localize with microtubule-associated protein 1A/1 B light chain 3 B (LC3) and lysosomal-associated membrane protein-1 (LAMP-1) in LM-treated astrocytes, coinciding with lysosomal acidification. These results indicate that the continuous buildup of LDs in astrocytes residing in lipid-enriched environments may be attributed to disruptions caused by LM in mitochondrial and lysosomal functions. Such disruptions could potentially impede the supportive role of astrocytes in neuronal function. [Display omitted] • Inadequate lipid droplet accumulation reduces the viability of astrocytic cells. • Increased lipid intake impairs mitochondrial function and autophagy efficiency in astrocytes. • A high-lipid microenvironment enhances lysosomal acidification in astrocytic cells. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), gradually recognized as an untreatable neurodegenerative disorder, has been considered to be closely associated with Aβ plaques, which consist of β-amyloid protein (Aβ) and is one of the crucial pathological features of AD. There are no obvious symptoms in the initial phase of AD, and thus the therapeutic interventions are important for early diagnosis of AD. Moreover, recent researches have indicated that lipid droplets might serve as a potential ancillary biomarker, and its viscosity changes are closely associated to the pathological process of AD. Herein, two newly fluorescent probes 5QSZ and BQSZ have been developed and synthesized for identifying Aβ aggregates and detecting the viscosity of lipid droplet. After selectively binding to Aβ aggregates, 5QSZ and BQSZ exhibited linear and obvious fluorescence enhancements (32.58 and 36.70 folds), moderate affinity (K d = 268.0 and 148.6 nM) and low detection limits (30.11 and 65.37 nM) in aqueous solutions. Further fluorescence staining of 5QSZ on brain tissue sections of APP/PS1 transgenic mouse exhibited the higher selectivity of 5QSZ towards Aβ aggregates locating at the core of the plaques. Furthermore, 5QSZ and BQSZ displayed strong linear fluorescence emission enhancements towards viscosity changes and would be utilized to monitor variation in cellular viscosity induced by LPS or monensin. These two probes were non-cytotoxic and showed good localization in lipid droplets. Therefore, 5QSZ and BQSZ could serve as potential bi-functional fluorescent probes to image Aβ aggregates and monitor the viscosity of lipid droplets, which have significant implications for the early diagnosis and progression of AD. [Display omitted] • A series of BODIPY-based probes for Aβ aggregates were developed by extending the conjugation system. • These probes exhibit good selectivity and high affinity towards Aβ aggregates. • These probes can detect viscosity changes and target lipid droplets. • 5QSZ could image Aβ aggregates and monitor viscosity within lipid droplets. [ABSTRACT FROM AUTHOR]

The aberrant deposition of lipid droplets (LDs) is a pivotal feature in foam cells formation and has significant implications for understanding the pathogenesis and early diagnosis of atherosclerosis (AS). In this study, we engineered a fluorescent probe, PyTPA-LD, for the reliable tracking of intracellular LDs. Through the application of PyTPA-LD, we monitored LD generation during the transition of macrophages induced by oxidized low-density lipoprotein (ox-LDL) into foam cells. Furthermore, we observed dynamic changes in lysosomes and LDs during lipophagy in this transitional process. Our study unveiled the dual role of lysosomes in LD formation: the degradation and release of ox-LDL within lysosomes promote LDs formation, while concurrently, lipophagy contributes to LDs clearance. This novel perspective provides a comprehensive understanding of the dynamic generation and clearance of LDs during foam cells formation. This work offers crucial insights into the pathogenic mechanisms underlying AS, deepening our understanding of AS development and providing valuable insights into lipid metabolism-related diseases. • A fluorescent probe was successfully developed to target LDs by molecular structure engineering and optimization. • This probe can be used to observe and validate LDs involvement in autophagy and transport in situ and in real-time. • During LDs formation, the dual role of lysosomes was revealed in macrophage transition induced by ox-LDL into foam cells. • This work significantly advances our understanding of the pathogenic mechanisms underlying atherosclerosis. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are spherical organelles that localize in the cytosol of eukaryotic cells. Different proteins are embedded on the surface of LDs, so LDs play a vital role in the physiological activities of cells. The dysregulation of LDs is associated with various human diseases, such as diabetes and obesity. Therefore, it is essential to develop a fluorescent dye that labels LDs to detect and monitor illnesses. In this study, we developed the compound BDAA12C for staining LDs in cells. BDAA12C exhibits excellent LD specificity and low toxicity, enabling us to successfully stain and observe the fusion of LDs in A549 cancer cells. Furthermore, we also successfully distinguished A549 cancer cells and MRC-5 normal cells in a co-culture experiment and in normal and tumour tissues. Interestingly, we found different localizations of BDAA12C in well-fed and starved A549 cancer cells and consequently illustrated the transfer of fatty acids (FAs) from LDs to mitochondria to supply energy for β-oxidation upon starvation. Therefore, BDAA12C is a promising LD-targeted probe for cancer diagnosis and tracking lipid trafficking within cells. BDAA12C is a novel fluorescence probe for recognizing and tracking lipids trafficking in starved and well-fed cancer cells, and BDAA12C shows excellent potential as a cancer diagnostic probe. [Display omitted] • BDAA12C exhibits strong emission in low-polarity solvents • BDAA12C generates bright emission in the lipid droplets of cells • BDAA12C can be used to monitor the trafficking of lipid droplets • BDAA12C accumulates in both lipid droplets and mitochondria of starved cells • BDAA12C can be used to recognize cancer cells as well as tumour tissue [ABSTRACT FROM AUTHOR]

[Display omitted] • LD-VP emits fluorescence at 520 nm in dioxane and 600 nm in viscous media without any interference from biological entities. • The LD-VP probe is pH-independent. • The quantum yield of probe LD-VP has changed from 0.5 % to 30% as the viscosity rises from 0.9 cP to 953 cP. • Probe LD-VP has provided green images in nonpolar intracellular milieu detection and red images for high viscosity. • Probe LD-VP concurrently labeled mitochondria, lysosomes, and lipid droplets in red and green channels based on intracellular viscosity and polarity. The viscosity and polarity of cells are inherent physical parameters, and changes to these attributes are frequently linked to malfunctioning conditions or different diseases. Cancer cells often harbor elevated nonpolar lipid droplets (LDs), acting as energy reserves. The rise in lipid droplets (LDs) and viscosity, distinctive traits of cancer cells, has motivated us to develop a fluorescent probe based on naphthalimide. The fluorescent marker LD-VP exhibits fluorescence signals at 520 nm in nonpolar dioxane and 600 nm in highly viscous glycerol. This implies that probe LD-VP can furnish details regarding cellular microviscosity and lipid droplets within live cells by providing dual-channel images. The probe LD-VP is chemically inert and harmless, enabling its safe utilization in live cell imaging. We conducted fluorescence imaging based on viscosity using probe LD-VP in the red channel, which is found to be co-localized in both mitochondria and lysosomes. Moreover, the probe effectively marks lipid droplets in the green channel. The probe LD-VP represents a distinctive fluorescent tool capable of monitoring both viscosity and lipid droplet expression in live cells. This tool holds the potential for visualizing physiological abnormalities or pathological conditions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two BODIPY-based NIR fluorescent probes were developed. • These fluorescent probes showed turn-on fluorescence upon viscosity change. • BSZ-Ph and BSZ-R exhibited organelle-targeting properties. • BSZ-R was utilized for cellular-level imaging of lipid droplets and lysosomes. Microenvironmental viscosity is a crucial parameter for biological systems, and its abnormal fluctuations are closely associated with various functional disorders and diseases. However, it is still important and urgent to develop improved near-infrared fluorescent probes for micro-viscosity with dual-organelle targeting properties, low background noise, and high sensitivity. Herein, two BODIPY-based small-molecule fluorescent probes were designed and synthesized, which were explored for their viscosity- and polarity-responsive properties, and were further applied to imaging sub-cellular viscosity in living cells. Interestingly, BSZ-Ph and BSZ-R displayed near-infrared fluorescence (more than 650 nm) and were sensitive to environmental viscosity and polarity due to the introduction of a benzothiazole at the 2-position and electron-rich aniline groups at the 5-position of the BODIPY core, respectively. The fluorescence intensity increased exponentially with the viscosity changes. Furthermore, the probe BSZ-Ph could successfully target lipid droplets and image cellular viscosity changes by treating lipopolysaccharides (LPS) and nystatin. Comparatively, the probe BSZ-R could successfully target the dual organelles of lipid droplets and lysosomes and image cellular viscosity changes by treating LPS and monensin. Therefore, in this work, we reported two new BODIPY-based near-infrared fluorescent probes, BSZ-Ph and BSZ-R, for cellular viscosity imaging, which could target lipid droplets and the dual organelles of lysosomes and lipid droplets, respectively. The study could provide a reference for the future development of fluorescent probes for viscosity in lipid droplets and lysosomes. [ABSTRACT FROM AUTHOR]

Lipid deposition has been considered one of the key factors in the occurrence of valvular heart disease (VHD) and a great potential target for the diagnosis of VHD. However, the development of lipid imaging technologies and efficient lipid specific probes is in urgent demand. In this work, we have prepared a lipid droplets (LDs) targeted fluorescence probe CPTM based on a push-pull electronic structure for the imaging of diseased aortic valves. CPTM showed obvious twisted intramolecular charge transfer (TICT) effect and its emission changed from 600 nm in water to 508 nm in oil. CPTM not only exhibited good biocompatibility and high photostability, but also impressive LDs specific imaging performance in human primary valvular interstitial cells and human diseased aortic valves. Moreover, the dynamic changes of intracellular LDs could be monitor in real-time after staining with CPTM. These results were expected to offer new ideals for the designing of novel LDs specific probes for further bioimaging applications. A lipid droplet activated color switchable probe CPTM with color change from red to green is prepared for the imaging of lipid deposition in human diseased heart valves. [Display omitted] • A lipid droplet activated color switchable probe CPTM was developed. • CPTM showed obvious AIE effect and lipid enhanced emission. • CPTM could specifically light up intracellular lipid droplets. • Lipid deposition in human diseased aortic valve leaflet could be observed by staining with CPTM. [ABSTRACT FROM AUTHOR]

Lipid droplets (LD) are highly dynamic organelles specialized for the regulation of energy storage and cellular homeostasis. LD consist of a neutral lipid core surrounded by a phospholipid monolayer membrane with embedded proteins, most of which are involved in lipid homeostasis. In this study, we focused on one of the major LD proteins, sterol C24-methyltransferase, encoded by ERG6. We found that the absence of Erg6p resulted in an increased accumulation of yeast perilipin Pet10p in LD, while the disruption of PET10 was accompanied by Erg6p LD over-accumulation. An observed reciprocal enrichment of Erg6p and Pet10p in pet10Δ and erg6Δ mutants in LD, respectively, was related to specific functional changes in the LD and was not due to regulation on the expression level. The involvement of Pet10p in neutral lipid homeostasis was observed in experiments that focused on the dynamics of neutral lipid mobilization as time-dependent changes in the triacylglycerols (TAG) and steryl esters (SE) content. We found that the kinetics of SE hydrolysis was reduced in erg6Δ cells and the mobilization of SE was completely lost in mutants that lacked both Erg6p and Pet10p. In addition, we observed that decreased levels of SE in erg6Δpet10Δ was linked to an overexpression of steryl ester hydrolase Yeh1p. Lipid analysis of erg6Δpet10Δ showed that PET10 deletion altered the composition of ergosterol intermediates which had accumulated in erg6Δ. In conclusion, yeast perilipin Pet10p functionally interacts with Erg6p during the metabolism of ergosterol. • The accumulation of Erg6p and Pet10p in pet10Δ and erg6Δ is reciprocal. • The disruption of PET10 affects several phenotypes of the erg6Δ cells. • The mobilization of steryl esters in erg6Δpet10Δ is completely lost. • The disruption of PET10 in erg6Δ alters the composition of ergosterol intermediates. • Decreased levels of SE in erg6Δpet10Δ is linked with the overexpression of steryl ester hydrolase Yeh1p. [ABSTRACT FROM AUTHOR]

Singlet oxygen (1O 2) and hypochlorite (ClO-) are two important reactive oxygen species. They coexist in living systems and can be interconverted in organisms, being involved in a variety of pathophysiological processes. Lipid droplets (LDs) are organelles that transport and store lipids, and 1O 2 and ClO- tend to destroy unsaturated lipids, leading to lipid oxidation and causing a range of diseases. Here we proposed the first dual-response fluorescent probe DBCC that can simultaneously distinguish 1O 2 and ClO- within LDs. The probe is almost non-fluorescent, while significant fluorescence enhancement can be observed in the blue and green channels after treatment with 1O 2 and ClO-, respectively. With the excellent properties of high sensitivity, good selectivity and wide tolerance range, the probe DBCC has been successfully used to detect 1O 2 and ClO- in HepG2 cells and zebrafish, and faultlessly realized endogenous and exogenous 1O 2 and ClO- imaging in LDs. This work provides a powerful analytical tool for further investigating the levels of 1O 2 and ClO- in LDs and associated diseases. [Display omitted] • A dual-response fluorescent probe DBCC based on Nile red skeleton was developed. • The probe can detect 1O2 and ClO- simultaneously. • The probe exhibits excellent lipid droplets targeting ability. • 1O2 and ClO- imaging in vivo and in vitro were achieved. [ABSTRACT FROM AUTHOR]

Pro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+→AMPK→ULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM. [Display omitted] • MM requires LCFA for metabolism and survival especially under stress conditions • Pro-survival signals regulate LCFA availability for metabolism through lipophagy • Blocking lipophagy sensitizes MM to chemotherapy Peng et al. show that multiple myeloma cells rely on LCFA for metabolism to overcome stress. Pro-survival signals regulate lipophagy to control LCFA availability. Therefore, blocking lipophagy can sensitize cancer cells to therapy and improve treatment efficacy. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) polarity is intricately linked to diverse biological processes and diseases. The visualization of LDs-polarity is of vital importance but challenging due to the lack of high-specificity, high-sensitivity and large-Stokes shift probes for real-time tracking LDs-polarity in biological systems. Four D-π-A based fluorescent probes (TPA-TCF1-TPA-TCF4) have been developed by combining tricyanofuran (an electron acceptor, A) and triphenylamine (an electron donor, D) derivatives with different terminal groups. Among them, TPA-TCF1 and TPA-TCF4 exhibit excellent polar sensitivity, large Stokes shift (≥182 nm in H 2 O), and efficient LDs targeting ability. In particular, TPA-TCF4 is capable of monitoring the change of LDs-polarity during ferroptosis, inflammation, apoptosis of cancer cell, and fatty liver. All these features render TPA-TCF4 a versatile tool for pharmacodynamic evaluation of anti-cancer drugs, in-depth understanding of the biological effect of LDs on ferroptosis, and medical diagnosis of LDs-polarity related diseases. [Display omitted] • TPA-TCF4 has a large Stokes shift and targets LDs via a "washing-free" procedure. • TPA-TCF4 can reflect the change of LDs polarity in ferroptosis and inflammation. • TPA-TCF4 can be used to evaluate the efficacy of anticancer drugs. • TPA-TCF4 can detect fatty liver at tissue, organ and even in vivo levels. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a disorder that affects lipid metabolism. Abnormalities in the lipid droplets (LDs) can lead to disturbances in lipid metabolism, which is a significant feature of diabetic patients. Nevertheless, the correlation between diabetes and the polarity of LDs has received little attention in the scientific literature. In order to detect LDs polarity changes in diabetes illness models, we created a new fluorescence probe LD-DCM. This probe has a stable structure, high selectivity, and minimal cytotoxicity. The probe formed a typical D-π-A molecular configuration with triphenylamine (TPA) and dicyanomethylene-4H-pyran (DCM) as electron donor and acceptor parts. The LD-DCM molecule has an immense solvatochromic effect (λ em = 544–624 nm), fluorescence enhancement of around 150 times, and a high sensitivity to polarity changes within the linear range of Δ f = 0.28 to 0.32, all due to its distinctive intramolecular charge transfer effect (ICT). In addition, LD-DCM was able to monitor the accumulation of LDs and the reduction of LDs polarity in living cells when stimulated by oleic acid, lipopolysaccharide, and high glucose. More importantly, LD-DCM has also been used effectively to detect polarity differences in organs from diabetic, drug-treated, and normal mice. The results showed that the liver polarity of diabetic mice was lower than that of normal mice, while the liver polarity of drug-treated mice was higher than that of diabetic mice. We believe that LD-DCM has the potential to serve as an efficient instrument for the diagnosis of disorders that are associated with the polarity of LDs. The first visualization of the polarity of lipid droplets in diabetic liver injury using fluorescence imaging. [Display omitted] • The fluorescent probe LD-DCM was established firstly to detect changes in hepatic lipid droplet polarity. • Probe LD-DCM was used to image lipid droplets in living cells, i n vitro organs and diabetic mice. • Probe LD-DCM revealed the decrease of LDs polarity in diabetic mice for the first time. [ABSTRACT FROM AUTHOR]

Mechanical forces play a crucial role in cellular processes, including ferroptosis, a form of regulated cell death associated with various diseases. However, the mechanical aspects of organelle lipid droplets (LDs) during ferroptosis are poorly understood. In this study, we designed and synthesized a fluorescent probe, TPE-V1 , to enable real-time monitoring of LDs' viscosity using a dual-channel fluorescence-on model (red channel at 617 nm and NIR channel at 710 nm). The fluorescent imaging of using TPE-V1 was achieved due to the integrated mechanisms of the twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE). Through dual-emission channel fluorescence imaging, we observed the enhanced mechanical energy of LDs triggering cellular mechanosensing, including ferroptosis and cell deformation. Theoretical calculations confirmed the probe's behavior, showing that high-viscosity media prevented the rotation processes and restored fluorescence quenching in low viscosity. These findings suggest that our TICT-TPE design strategy provides a practical approach to study LDs' mechanical properties during ferroptosis. This development enhances our understanding of the interplay between mechanical forces and LDs, contributing to the knowledge of ferroptotic cell death and potential therapeutic interventions targeting dysregulated cell death processes. [Display omitted] • Probe TPE-V1 could precisely monitor LDs viscosity through red and NIR channels. • Mechanism of TPE-V1 for viscosity based on TICT-AIE was confirmed by DFT calculation. • Probe TPE-V1 has excellent selectivity and sensitivity towards LDs viscosity. • LDs mechanical property changes during ferroptosis was monitored by red-NIR channels. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) or hepatotoxicity is a significant concern for public health. However, relying on a single biomarker for early DILI diagnosis poses a high risk of false positives. In this study, we reported a near-infrared fluorescent probe (BCOU-S), which enables independent visualization of LDs status and ONOO fluctuations. BCOU-S was constructed by combining a π-extended coumarin core as the NIR fluorophore and a methyl thioether group as the ONOO recognition site. BCOU-S could emit 655 nm NIR fluorescence excited at 518 nm, with a low detection limit of 27 nM and a large Stokes shift of 137 nm. The response mechanism to ONOO was confirmed by molecular orbital density function theory (DFT) and time-dependent DFT (TD-DFT) calculations. BCOU-S monitors LDs status through co-localization, oleic acid (OA) incubation, and starvation induction experiments. It sensitively distinguishes subtle changes in ONOO induced by different drugs in DILI cell models. In the acetaminophen (APAP)-induced DILI model, BCOU-S reveals significant LDs accumulation and increase in ONOO levels, establishing a clear time-effect and dose-effect relationship. Simultaneously monitoring ONOO levels and LDs accumulation, BCOU-S proves to be a more sensitive and effective tool for early DILI prevention, effectively avoiding false positives caused by changes in a single parameter. BCOU-S is a useful tool for further monitoring early DILI development. [Display omitted] • A LDs-targeted and ONOO-responsive NIR probe contains a π-extended coumarin core. • BCOU-S responses ONOO within 2 s and with a detection limit of 27 nM. • BCOU-S can visualize LDs status and ONOO fluctuations in DILI. [ABSTRACT FROM AUTHOR]

[Display omitted] • The structure and biological functions of LDs and their mode of interaction with other organelles are briefly described. • Fluorescent probes that focus on the network of interactions between LDs and other organelles were summarized. • Fluorescent probes reviewed are divided into dual-targeted and multi-targeted based on the number of organelles targeted. • Challenges and directions for developing multi-organelle LDs-associated fluorescent probes are discussed. Lipid droplets, as the centre of lipid metabolism, interact with the endoplasmic reticulum, mitochondria, lysosome, nucleus and other organelles to maintain the body's energy balance through vesicle transport or membrane contact. Disruption of the interaction process will lead to the development of lipid metabolism-related diseases. In recent years, many fluorescent probes have been developed to visually follow the dynamic interaction process visually between lipid droplets and other organelles. Existing reviews on lipid droplets fluorescent probes are mainly categorised and reviewed in terms of the emission band of probes, mother fluorophores and design strategies. However, probes that focus on the interactions between lipid droplets and other organelles can provide further insight into the whole process from lipid droplets formation to transformation as well as the mechanisms of diseases related to lipid metabolism. This paper mainly reviews the progress of fluorescent probes targeting lipid droplets interactions with other organelles in the last five years and is divided into dual-targeted and multi-targeted sections based on the number of targeted organelles. The focus is on the biological contacts and dynamic interaction processes between lipid droplet-centred organelles observed by fluorescence imaging with dual-targeted and multi-targeted probes in the article. The targeting groups and reaction sites of the probes are marked in the figure. Moreover, the paper briefly describes the structure and biological functions of lipid droplets and their connections with other organelles. Perhaps in addition to the imaging performance of the probes, we believe that the use of precision instruments to provide high spatio-temporal resolution and reliable results is also a key factor in observational studies. Finally, we summarize the development prospect of multi-color multi-targeted fluorescent probes related to lipid droplets. We expect to bring novel thinking to the design of lipid droplet fluorescent probes and provide new ideas for exploring diagnostic and therapeutic options for lipid droplet-related diseases. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are the main organelles for lipid storage, and their surfaces contain unique proteins with diverse functions, including those that facilitate the deposition and mobilization of LD lipids. Among organelles, LDs have an unusual structure with an organic, hydrophobic oil phase covered by a phospholipid monolayer. The unique properties of LD monolayer surfaces require proteins to localize to LDs by distinct mechanisms. Here we review the two pathways known to mediate direct LD protein localization: the CYTOLD pathway mediates protein targeting from the cy tosol to LD s, and the ERTOLD pathway functions in protein targeting from the e ndoplasmic r eticulum to LD s. We describe the emerging principles for each targeting pathway in animal cells and highlight open questions in the field. Lipid droplet (LD) organelles contain specific proteins, including metabolic enzymes, that differ among cell types. Proteins targeting the monolayer surface of lipid droplets do not follow the same principles as proteins targeting bilayer membranes. The targeting of proteins to lipid droplet surfaces is governed by the biophysical features of their unique oil–water interface. LD protein targeting occurs via two major pathways: CYTOLD and ERTOLD targeting. Elucidating the principles driving these protein targeting pathways has implications for further understanding physiology and metabolic diseases. [ABSTRACT FROM AUTHOR]

Fluid interfaces, i.e. the boundary layer of two liquids or a liquid and a gas, play a vital role in physiological processes as diverse as visual perception, oral health and taste, lipid metabolism, and pulmonary breathing. These fluid interfaces exhibit a complex composition, structure, and rheology tailored to their individual physiological functions. Advances in interfacial thin film techniques have facilitated the analysis of such complex interfaces under physiologically relevant conditions. This allowed new insights on the origin of their physiological functionality, how deviations may cause disease, and has revealed new therapy strategies. Furthermore, the interactions of physiological fluid interfaces with exogenous substances is crucial for understanding certain disorders and exploiting drug delivery routes to or across fluid interfaces. Here, we provide an overview on fluid interfaces with physiological relevance, namely tear films, interfacial aspects of saliva, lipid droplet digestion and storage in the cell, and the functioning of lung surfactant. We elucidate their structure-function relationship, discuss diseases associated with interfacial composition, and describe therapies and drug delivery approaches targeted at fluid interfaces. Fluid interfaces are inherent to all living organisms and play a vital role in various physiological processes. Examples are the eye tear film, saliva, lipid digestion & storage in cells, and pulmonary breathing. These fluid interfaces exhibit complex interfacial compositions and structures to meet their specific physiological function. We provide an overview on physiological fluid interfaces with a focus on interfacial phenomena. We elucidate their structure-function relationship, discuss diseases associated with interfacial composition, and describe novel therapies and drug delivery approaches targeted at fluid interfaces. This sets the scene for ocular, oral, or pulmonary surface engineering and drug delivery approaches. [Display omitted] [ABSTRACT FROM AUTHOR]

Currently, it has been well established that growth, bodily form, physiological responses, and metabolic features of teleost fish may display sexual difference during intensive farming. Herein, the study aims to mainly examine the disparities of histomorphological and molecular responses in representative tissues liver and caudal vein blood from male and female cultured largemouth bass (Micropterus salmoides) juveniles by tracking a growth period of 135 days for reaching sexual maturity. The liver indices of a majority of the females, such as mass ratio of hepatic and visceral tissues (MRHV), hepatosomatic index (HSI), and hepatic lipid droplet abundance, were obviously greater than the males. Observational outcomes on size and distribution of accumulated lipid droplets in the liver of the females were more obvious and distinct from the males. Hepatic transcriptome sequencing results also demonstrated that glycerophospholipid metabolism-related/lipid transport-related genes (e.g. chkb , vtg3), PPAR signaling pathway, and aromatic amino acids metabolism (e.g. tyrosine, phenylalanine) were more active in the females; whereas, genes or pathways related to long-chain lipid transport (e.g. slc27a6), fatty acid biosynthesis and decomposition (e.g. ptgdsa), tryptophan metabolism, and immunological/inflammatory responses (e.g. mst1), as well as mTOR/PI3K-Akt/FoxO/AMPK signaling pathways in the males, were more evidently up-regulated than the females. Serum non-targeted metabolomics results exhibited that 5-hydroxyindoleacetic acid (growth factor derivative) and adipoyl- l -carnitine (lipid transporter) in the males were higher in quantity while L-kynurenine (tryptophan metabolism) and l -carnitine (lipid transporter) in the females higher than the males. The findings preliminarily showed that activity of PPAR signaling pathway and high expression of chkb gene might be crucial mechanisms in gained hepatic lipids in the females, while the actions of metabolites l -carnitine/adipoyl- l -carnitine might be more conducive to lipid transport in the liver of the males. [Display omitted] • Molecular responses in liver/serum of male/female farmed largemouth bass were studied. • The liver indices (MRHV, HSI, lipid abundance) of a majority of females are higher. • PPAR signaling pathway might be a crucial mechanism in gained hepatic lipids in females. • mTOR/PI3K-Akt/FoxO/AMPK signaling pathways are significantly up-regulated in males. • Adipoyl- l -carnitine in males is higher in quantity, l -carnitine in females is higher. [ABSTRACT FROM AUTHOR]

The accumulation of lipid droplets (LDs) in aging and Alzheimer's disease brains is considered a pathological phenomenon with unresolved cellular and molecular mechanisms. Utilizing stimulated Raman scattering (SRS) microscopy, we observed significant in situ LD accumulation in microglia of tauopathy mouse brains. SRS imaging, combined with deuterium oxide (D 2 O) labeling, revealed heightened lipogenesis and impaired lipid turnover within LDs in tauopathy fly brains and human neurons derived from induced pluripotent stem cells (iPSCs). Transfer of unsaturated lipids from tauopathy iPSC neurons to microglia induced LD accumulation, oxidative stress, inflammation, and impaired phagocytosis. Neuronal AMP-activated protein kinase (AMPK) inhibits lipogenesis and promotes lipophagy in neurons, thereby reducing lipid flux to microglia. AMPK depletion in prodromal tauopathy mice increased LD accumulation, exacerbated pro-inflammatory microgliosis, and promoted neuropathology. Our findings provide direct evidence of native, aberrant LD accumulation in tauopathy brains and underscore the critical role of AMPK in regulating brain lipid homeostasis. [Display omitted] • Tauopathy neurons accumulate LDs • Tauopathy neurons release excess unsaturated lipids, taken up by microglia • LD-accumulating microglia are pro-inflammatory and impaired in phagocytosis • Neuronal AMPK inhibits LD accumulation in neurons and microglia Lipid droplets (LDs) accumulate in brains with Alzheimer's disease. Using stimulated Raman scattering (SRS) microscopy, Li et al. discovered that tauopathy neurons generate excess unsaturated lipids that are transferred to microglia where LDs accumulate, promoting neuroinflammation. Neuronal AMPK inhibits LD accumulation cell-autonomously and non-cell-autonomously, ameliorating microgliosis and neurotoxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Brominated alkyl endows a red-emissive probe G1 track LDs in a wash-free manner. • Probe G1 can localize LDs and monitor the dynamic of LDs in living HepG2 cells. • Probe G1 can diagnose LDs accumulation in fatty liver from NAFLD mice model. Lipid droplets (LDs) participate in lipid storage and metabolism, which is a critical indication of metabolic diseases, like nonalcoholic fatty liver disease (NAFLD). Fluorescent probes have been extensively applied due to their excellent superiorities, but it is usually impossible to realize specific LDs-targeting by a simple bromination in a fluorescent probe. In current study, we developed two red-emissive probes (G1 and G2) that are condensed by isophorone and carbazole with or without a bromine substitution in alkyl group. Unexpectedly, G1 with brominated alkyl displayed specific targeting to LDs, while G2 with only alkyl chain exhibited no LDs-targeting effect. Subsequently, G1 was successfully applied to track LDs and their dynamics in living cells, and image LDs in livers of mice feeding high-fat diet. This study is a new paradigm for devising a fluorescent tool to trace LDs, which may provide a powerful tool for the early diagnosis of NAFLD. [ABSTRACT FROM AUTHOR]

• Adipose triglyceride lipase (ATGL) delayed endothelial LDs degradation. • LDs formation was associated with ATGL-dependent PGI 2 generation. • LDs and ATGL-dependent PGI 2 generation feature vascular inflammation response. [ABSTRACT FROM AUTHOR]