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This review presents a summary of recent progress in research on the N6-methyladenosine (m6A) modification and regulatory roles in hepatic lipid metabolism. As the most abundant internal modification of eukaryotic RNA, the m6A modification is a dynamic and reversible process of the m6A enzyme system, which includes writers, erasers, and readers. m6A methylation depressed lipid synthesis and facilitated lipolysis in liver. The depletion of m6A methyltransferase Mettl14/Mettl3 raised fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), acetyl-CoA carboxylase (ACC), and elongase of very long chain fatty acids 6 (ELOVL6) in rodent liver, causing increases in liver weight, triglyceride (TG) production, and content in hepatocytes. FTO catalyzed m6A demethylation and the suppression m6A reader YTHDC2 promoted hepatocellular TG generation and hepatic steatosis in C57BL/6 mice through sterol regulatory element-binding protein 1c (SREBP-1c) signaling pathway, which upregulated the lipogenic genes FAS, SCD1, ACC, recombinant acetyl coenzyme a carboxylase alpha, and cell death-inducing DNA fragmentation factor-like effector C (CIDEC). Furthermore, FTO overexpression did not only enhance mitochondrial fusion to impair mitochondrial function and lipid oxidation but also promoted lipid peroxidation, accompanied by excessive TG in hepatocytes and rodent liver. Elevated m6A modification potently suppressed hepatic lipid accumulation, while the shrinkage of m6A modification arose hepatic lipid deposition. These findings have highlighted the beneficial role of m6A RNA methylation in hepatic lipid metabolism, potentially protecting liver from lipid metabolic disorders. [ABSTRACT FROM AUTHOR]

• MK plays a double-edged sword role in human disease. • MK promotes the development of inflammation, oxidative stress and lipid metabolism. • MK have a positive effect on ischemic vascular lesions and cytoprotective. Midkine (MK) is a low molecular-weight protein that was first identified as the product of a retinoic acid-responsive gene involved in embryonic development. Recent studies have indicated that MK levels are related to various diseases, including cardiovascular disease (CVD), renal disease and autoimmune disease. MK is a growth factor involved in multiple pathophysiological processes, such as inflammation, the repair of damaged tissues and cancer. The pathophysiological roles of MK are diverse. MK enhances the recruitment and migration of inflammatory cells upon inflammation directly and also through induction of chemokines, and contributes to tissue damage. In lung endothelial cells, oxidative stress increased the expression of MK, which induced angiotensin-converting enzyme (ACE) expression and the consequent conversion from Ang I to Ang II, leading to further oxidative stress. MK inhibited cholesterol efflux from macrophages by reducing ATP-binding cassette transporter A1 (ABCA1) expression, which is involved in lipid metabolism, suggesting that MK is an important positive factor involved in inflammation, oxidative stress and lipid metabolism. Furthermore, MK can regulate the expansion, differentiation and activation of T cells as well as B-cell survival; mediate angiogenic and antibacterial activity; and possess anti-apoptotic activity. In this paper, we summarize the pathophysiological roles of MK in human disease. [ABSTRACT FROM AUTHOR]

This review aims to provide insight into the role of N6‐methyladenosine (m6A) modification in neoplastic immunity and subsequent tumorigenesis. m6A modification, which is catalyzed by methyltransferases, demethylases and reader proteins, has emerged as a widespread regulatory mechanism that controls immune‐related gene expression and immune reactions during tumorigenesis. Aberrant m6A modification changes the neoplastic immune response in multiple cancers by regulating immune cell infiltration, tumor‐promoting inflammation, immunosuppression, immune surveillance, and antitumor immune responses. m6A modification affects immune cell recruitment and cancer‐promoting inflammation in hepatocellular carcinoma (HCC) to alter the progression of HCC. m6A modification has been implicated in the infiltration of immune cells and the activation of immune pathways, changing the proliferation and metastasis of gastric cancer. Immune surveillance and the antitumor immune response in breast cancer were enhanced via m6A modification, which inhibited tumor proliferation. m6A modification participates in neoplastic immunoregulation to influence tumor progression. [ABSTRACT FROM AUTHOR]

Apolipoprotein A-I binding protein (AIBP), a secreted protein, has been shown to play a pivotal role in the development of atherosclerosis. The function of intracellular AIBP, however, is not yet well characterized. Here, we found that AIBP is abundantly expressed within human and mouse atherosclerotic lesions and exhibits a distinct localization in the inner membrane of mitochondria in macrophages. Bone marrow-specific AIBP deficiency promotes the progression of atherosclerosis and increases macrophage infiltration and inflammation in low-density lipoprotein receptor-deficient (LDLR−/−) mice. Specifically, the lack of mitochondrial AIBP leads to mitochondrial metabolic disorders, thereby reducing the formation of mitophagy by promoting the cleavage of PTEN-induced putative kinase 1 (PINK1). With the reduction in mitochondrial autophagy, macrophages polarize to the M1 proinflammatory phenotype, which further promotes the development of atherosclerosis. Based on these results, mitochondrial AIBP in macrophages performs an antiatherosclerotic role by regulating of PINK1-dependent mitophagy and M1/M2 polarization. 9wPYiwBcJkigAW4BX-B6DE Video Abstract [ABSTRACT FROM AUTHOR]

The underlying mechanisms of circular RNAs (circRNAs) in lipid metabolism regulation and the pathogenesis of lipid disorder diseases are clarified in this review. circRNAs are produced from host genes by back splicing and are mainly degraded by RNase L. circRNAs act as molecular sponges or scaffolds that bind with microRNAs or proteins and thus affect the intracorporeal processes of lipid metabolism. CircRNA_11897 and circSAMD4A facilitated adipogenesis while circH19 and circRNA_26852 accelerated adipolysis in adipose tissue. CircSAMD4A promoted the differentiation of preadipocytes, but circH19 and circFUT10 inhibited this differentiation. CircFUT10 also promoted the proliferation of preadipocytes. CiRS‐133 fostered the browning of white adipose tissue. CircACC1, circRNA_021412, circRNA_0046366, and circRNA_0046367 promoted the mitochondrial β‐oxidation of fatty acids in hepatocytes. CircRNA_021412 suppressed the synthesis of triglycerides in hepatocytes. CircScd1 inhibited hepatic lipid droplet formation. circ_0092317, circ_0003546, circ_0028198, circ_0092317, and circACC1 probably reduced cholesterol efflux from macrophages. circ_0037251 likely promoted lipid accumulation and inhibited lipophagy in macrophages. circRNAs participate in lipid metabolism regulation and affect the development of lipid disorder diseases. [ABSTRACT FROM AUTHOR]

This review summarizes and analyzes the updated information on the regulation of sortilin expression and its trafficking function. Evidence indicates that the expression and function of sortilin are closely regulated at four levels: DNA, messenger RNA (mRNA), protein, and trafficking function. DNA methylation, several mutations, and minor single‐nucleotide polymorphisms within DNA fragments affect the expression of SORT1 gene. A few transcription factors and microRNAs modulate its transcription as well as the splicing or stability of the mRNA. Moreover, several translation factors control the synthesis of sortilin protein, and posttranslational modifications affect its degradation processes. Multiple adaptor molecules modulate the sortilin trafficking function in the anterograde or retrograde pathway. Recent advances in the regulation of sortilin expression and function, and its related mechanisms will help the ongoing research related to sortilin and promote future clinical application via sortilin intervention. [ABSTRACT FROM AUTHOR]

• What is Insig-1. • Insig-1 in lipid metabolism. • Mechanisms of Insig-1 in lipid metabolism. • Insig-1 in lipid disorders. Growing evidence has demonstrated that Insig-1 is intricately involved in lipid metabolism regulation and the progression of lipid disorders. Our review summarizes updated information on the role and underlying mechanisms of Insig-1 in lipid metabolism dyshomeostasis and lipid disorders. As a member of the insulin-induced gene family, insulin-induced gene 1 (Insig-1) is a six-span transmembrane protein embedded in the endoplasmic reticulum (ER) membrane. Insig-1 is widely involved in the maintenance of intracellular lipid metabolism homeostasis by controlling the activation of sterol regulatory element-binding proteins (SREBPs) and the degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Growing experimental and clinical data have identified that Insig-1 reduces lipid accumulation in hepatocytes to relieve the development of nonalcoholic fatty liver disease (NAFLD), downregulates the plasma level of free cholesterol and protects β cells against lipotoxicity to alleviate diabetic dyslipidemia. In addition, Insig-1 suppresses adipogenesis and inhibits the differentiation of preadipocytes to prevent the occurrence of obesity. Insig-1 is a key regulatory factor that maintains intracellular lipid metabolism homeostasis and is a promising therapeutic target for lipid disorders. [ABSTRACT FROM AUTHOR]

This review aims to summarize and discuss the most recent advances in our understanding of the underlying mechanisms of the paradoxical effects of sortilin on lipid metabolism. The vacuolar protein sorting 10 protein (Vps10p) domain in the sortilin protein is responsible for substrate binding. Its cytoplasmic tail interacts with adaptor molecules, and modifications can determine whether sortilin trafficking occurs via the anterograde or retrograde pathway. The complicated trafficking behaviors likely contribute to the paradoxical roles of sortilin in lipid metabolism. The anterograde pathway of sortilin trafficking in hepatocytes, enterocytes, and peripheral cells likely causes an increase in plasma lipid levels, while the retrograde pathway leads to the opposite effect. Hepatocyte sortilin functions via the anterograde or retrograde pathway in a complicated and paradoxical manner to regulate apoB‐containing lipoprotein metabolism. Clarifying the regulatory mechanisms underlying the trafficking behaviors of sortilin is necessary and may lead to artificial sortilin intervention as a potential therapeutic strategy for lipid disorder diseases. Conclusively, the paradoxical regulation of sortilin in lipid metabolism is likely due to its complicated trafficking behaviors. [ABSTRACT FROM AUTHOR]

B7 homolog 3 (B7‐H3) has been proven to be involved in tumorigenesis. An elucidation of its role and underlying mechanisms is essential to an understanding of tumorigenesis and the development of effective clinical applications. B7‐H3 is abnormally overexpressed in many types of cancer and is generally associated with a poor clinical prognosis. B7‐H3 inhibits the initiation of the "caspase cascade" by the Janus kinase/signal transducers and activators of transcription pathway to resist tumor cell apoptosis. B7‐H3 accelerates malignant proliferation by attacking the checkpoint mechanism of the tumor cell cycle through the phosphatidylinositol 3‐kinase and protein kinase B pathway. B7‐H3 reprograms the metabolism of glucose and lipids and transforms the metabolic flux of tumor cells to promote tumorigenesis. B7‐H3 induces abnormal angiogenesis by recruiting vascular endothelial growth factor and matrix metalloproteinase to tumor lesions. B7‐H3 strongly promotes tumorigenesis through antiapoptotic, pro‐proliferation, metabolism reprogramming, and pro‐angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract Increased plasma triglyceride serves as an independent risk factor for cardiovascular disease (CVD). Lipoprotein lipase (LPL), which hydrolyzes circulating triglyceride, plays a crucial role in normal lipid metabolism and energy balance. Hypertriglyceridemia is possibly caused by gene mutations resulting in LPL dysfunction. There are many factors that both positively and negatively interact with LPL thereby impacting TG lipolysis. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a newly identified factor, appears essential for transporting LPL to the luminal side of the blood vessel and offering a platform for TG hydrolysis. Numerous lines of evidence indicate that GPIHBP1 exerts distinct functions and plays diverse roles in human triglyceride-rich lipoprotein (TRL) metabolism. In this review, we discuss the GPIHBP1 gene, protein, its expression and function and subsequently focus on its regulation and provide critical evidence supporting its role in TRL metabolism. Underlying mechanisms of action are highlighted, additional studies discussed and potential therapeutic targets reviewed. Highlights • GPIHBP1, as a transporting and stabilizing role, is essential for the complete enzyme function of LPL. • Multiple factors regulate GPIHBP1 in both physiological and pathological process of TRL metabolism. • GPIHBP1 deficiency is related with TRL dysbolism-related diseases. [ABSTRACT FROM AUTHOR]

The present review provides a summary of recent evidence of sortilin expression, function, and regulation and its implications in lipid metabolism and development of lipid disorder diseases. As a member of the vacuolar protein sorting 10 protein (Vps10p) receptor family, sortilin mediates intracellular trafficking of diverse endogenous or exogenous protein substrates between the trans-Golgi network (TGN) and plasma membrane compartments. Recent studies reveal that sortilin regulates the expression of lipid genes, plasma lipid level, and the development of lipid disorder diseases. Sortilin promotes atherogenesis by regulating hepatic very low density lipoprotein (VLDL) secretion and plasma lipid level and subsequently macrophage lipid accumulation. Sortilin deficiency is caused by accelerated proteasome degradation under insulin resistance conditions and is thereby implicated in the hyperlipidemia of type 2 diabetes mellitus (T2DM). Sortilin facilitates hepatic cholesterol accumulation by inhibiting hepatic cholesterol catabolism, which promotes the development of nonalcoholic fatty liver disease (NAFLD). Sortilin plays an important role in lipid metabolism and represents a promising therapeutic target for lipid disorder diseases. [ABSTRACT FROM AUTHOR]