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Naked mole‐rats (NMRs) (Heterocephalus glaber) are highly social and subterranean rodents with large communal colonies in burrows containing low oxygen levels. The inhibition of severe hypoxic conditions is of particular interest to this study. To understand the mechanisms that facilitate neuronal preservation during hypoxia, we investigated the proteins regulating hypoxia tolerance in NMR hippocampal neurons. Caveolin‐1 (Cav‐1), a transmembrane scaffolding protein, confers prosurvival signalling in the central nervous system. The present study aimed to investigate the role of Cav‐1 in hypoxia‐induced neuronal injury. Western blotting analysis and immunocytochemistry showed that Cav‐1 expression was significantly upregulated in NMR hippocampal neurons under 8% O2 conditions for 8 h. Cav‐1 alleviates apoptotic neuronal death from hypoxia. Downregulation of Cav‐1 by lentiviral vectors suggested damage to NMR hippocampal neurons under hypoxic conditions in vitro and in vivo. Overexpression of Cav‐1 by LV‐Cav‐1 enhanced hypoxic tolerance of NMR hippocampal neurons in vitro and in vivo. Mechanistically, the levels of hypoxia inducible factor‐1α (HIF‐1α) are also increased under hypoxic conditions. After inhibiting the binding of HIF‐1α to hypoxia response elements in the DNA by echinomycin, Cav‐1 levels were downregulated significantly. Furthermore, chromatin immunoprecipitation assays showed the direct role of HIF1α in regulating the expression levels of Cav‐1 in NMR hippocampal neurons under hypoxic conditions. These findings suggest that Cav‐1 plays a critical role in modulating the apoptosis of NMR hippocampal neurons and warrant further studies targeting Cav‐1 to treat hypoxia‐associated brain diseases. [ABSTRACT FROM AUTHOR]

Objectives: To assess the association between altered expression of caveolin-1 and p53/p21, as indicatives of cellular senescence, in preeclamptic placenta.Study Design: Placental tissues and serum were collected from rats (Sham and reduced uterine perfusion pressure group) at 18.5 days post coitum and humans (normotensive pregnant and preeclampsia groups). The concentration and expression of caveolin-1 were measured in the collected tissues, and the correlation between p53 and p21 expression was evaluation.Main Outcome Measures: Placental mRNA expression and serum concentration of caveolin-1 were measured using qRT-PCR and ELISA, respectively. Altered expressions of caveolin-1 and p53/p21 were revealed and quantified by immunohistochemistry. The association between these changes was investigated using correlation analysis.Results: Placental mRNA expressions and serum concentrations of caveolin-1 were significantly decreased in reduced uterine perfusion pressure and preeclampsia groups. The expressions of caveolin-1 and p53/ p21 were significantly altered in placenta complicated with preeclampsia. Correlation analysis revealed a significant inverse association between changes in caveolin-1 and p53/p21. Subsequently, these results were obtained by investigating the preeclampsia onset time.Conclusion: These results revealed that the expression of caveolin-1 profoundly decreases in the placenta and serum of preeclampsia. These factors contribute to the mechanism of accelerated cellular senescence in placenta, which is one of the various etiologies of preeclampsia. [ABSTRACT FROM AUTHOR]

The skin is the outermost layer and largest organ in the human body. Since the skin interfaces with the environment, it has a variety of roles, including providing a protective barrier against external factors, regulating body temperature, and retaining water in the body. It is also involved in the immune system, interacting with immune cells residing in the dermis. Caveolin-1 (CAV-1) is essential for caveolae formation and has multiple functions including endocytosis, lipid homeostasis, and signal transduction. CAV-1 is known to interact with a variety of signaling molecules and receptors and may influence cell proliferation and migration. Several skin-related disorders, especially those of the inflammatory or hyperproliferative type such as skin cancers, psoriasis, fibrosis, and wound healing, are reported to be associated with aberrant CAV-1 expression. In this review, we have explored CAV-1 involvement in skin physiology and skin diseases. [ABSTRACT FROM AUTHOR]

Background: Caveolae are invaginated plasma membrane domains of 50–100 nm in diameter involved in many important physiological functions in eukaryotic cells. They are composed of different proteins, including the membrane-embedded caveolins and the peripheric cavins. Caveolin-1 has already been expressed in various expression systems (E. coli, insect cells, Toxoplasma gondii, cell-free system), generating intracellular caveolin-enriched vesicles in E. coli, insect cells and T. gondii. These systems helped to understand the protein insertion within the membrane and its oligomerization. There is still need for fundamental insights into the formation of specific domains on membrane, the deformation of a biological membrane driven by caveolin-1, the organization of a caveolar coat, and the requirement of specific lipids and proteins during the process. The aim of this study was to test whether the heterologously expressed caveolin-1β was able to induce the formation of intracellular vesicles within a Gram+ bacterium, Lactococcus lactis, since it displays a specific lipid composition different from E. coli and appears to emerge as a good alternative to E. coli for efficient overexpression of various membrane proteins. Results: Recombinant bacteria transformed with the plasmid pNZ-HTC coding for the canine isoform of caveolin-1β were shown to produce caveolin-1β, in its functional oligomeric form, at a high expression level unexpected for an eukaryotic membrane protein. Electron microscopy revealed several intracellular vesicles from 30 to 60 nm, a size comparable to E. coli h-caveolae, beneath the plasma membrane of the overexpressing bacteria, showing that caveolin-1β is sufficient to induce membrane vesiculation. Immunolabelling studies showed antibodies on such neo-formed intracellular vesicles, but none on plasma membrane. Density gradient fractionation allowed the correlation between detection of oligomers on Western blot and appearance of vesicles measurable by DLS, showing the requirement of caveolin-1β oligomerization for vesicle formation. Conclusions: Lactococcus lactis cells can heterologously overexpress caveolin-1β, generating caveolin-1β enriched intracellular neo-formed vesicles. These vesicles might be useful for potential co-expression of membrane proteins of pharmaceutical interest for their simplified functional characterization. [ABSTRACT FROM AUTHOR]

Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 × 10-8). These noncoding variants together significantly contributed to the linkage evidence (P < 10-3). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity. [ABSTRACT FROM AUTHOR]

Aims: Iron metabolism is involved in many biological processes in the brain. Alterations in iron homeostasis have been associated with several neurodegenerative disorders. Instead of stroke and ischemic heart disease, dementia has become the second leading cause of mortality among the type 2 diabetes mellitus (T2DM) population. Therefore, we attempted to investigate the role of ferroptosis in diabetes-associated cognitive dysfunction (DACD). Results: We evaluated ferroptosis hallmarks in the hippocampus of T2DM (high-fat diet/streptozotocin, HFD/STZ) mice, primary hippocampal neurons, as well as in the blood of patients. The results of Gene Set Enrichment Analysis showed significantly differentially expressed genes related to ferroptosis-related pathways between normal control (db/m) and leptin receptor-deficient (db/db) mice. Here, ferroptosis, mitochondrial dysfunction and cognitive impairment were revealed, and caveolin-1 (cav-1) was significantly downregulated in the hippocampus of T2DM (HFD/STZ) mice. In addition, ferrostatin-1 and cav-1 restoration neutralized ferroptosis-related symbolic changes, mitochondrial dysfunction, and improved cognitive dysfunction. Notably, the plasma levels of Fe2+ and 4-hydroxynonenal (4-HNE) in T2DM patients showed a tendency to increase compared with those in nondiabetic subjects, and the Fe2+ level was negatively correlated with the cognitive ability in T2DM subjects. Innovation: For the first time, this study suggested that ferroptosis promoted the progression of DACD induced by T2DM both in vivo and in vitro, and supported the clinical evidence for the correlation between ferroptosis and T2DM-related DACD, which provided new insights into the potential antioxidant effects of ferroptosis inhibitors and cav-1 on DACD. Conclusions: The overexpression of cav-1 may attenuate DACD by modulating neuronal ferroptosis-mediated mitochondrial homeostasis. We put cav-1 on the spotlight as a promising candidate to prevent DACD. Antioxid. Redox Signal. 37, 867–886. [ABSTRACT FROM AUTHOR]

Exposure to silica is a cause of pulmonary fibrosis disease termed silicosis, which leads to respiratory failure and ultimately death. However, what drives fibrosis is not fully elucidated and therapeutic options remain limited. Our previous RNA-sequencing analysis showed that the expression of caveolin-1 (CAV1) was downregulated in silica-inhaled mouse lung tissues. Here, we not only verified that CAV1 was decreased in silica-induced fibrotic mouse lung tissues in both messenger RNA and protein levels, but also found that CSP7, a functional peptide of CAV1, could attenuate pulmonary fibrosis in vivo. Further in vitro experiments revealed that CAV1 reduced the expression of Yes-associated protein 1(YAP1) and affected its nuclear translocation in fibroblasts. In addition, Glutaminase 1 (GLS1), a key regulator of glutaminolysis, was identified to be a downstream effector of YAP1. CAV1 could suppress the activity of YAP1 to decrease the transcription of GLS1, thereby inhibiting fibroblast activation. Taken together, our results demonstrated that CAV1 and its functional peptide CSP7 may be potential molecules or drugs for the prevention and intervention of silicosis. [ABSTRACT FROM AUTHOR]

Caveolin‐1 (Cav‐1) is an integral membrane protein present in all organelles, responsible for regulating and integrating multiple signals as a platform. Mitochondria are extremely adaptable to external cues in chronic liver diseases, and expression of Cav‐1 may affect mitochondrial flexibility in hepatic stellate cells (HSCs) activation. We previously demonstrated that exogenous expression of Cav‐1 was sufficient to increase some classical markers of activation in HSCs. Here, we aimed to evaluate the influence of exogenous expression and knockdown of Cav‐1 on regulating the mitochondrial plasticity, metabolism, endoplasmic reticulum (ER)‐mitochondria distance, and lysosomal activity in HSCs. To characterize the mitochondrial, lysosomal morphology, and ER‐mitochondria distance, we perform transmission electron microscope analysis. We accessed mitochondria and lysosomal networks and functions through a confocal microscope and flow cytometry. The expression of mitochondrial machinery fusion/fission genes was examined by real‐time polymerase chain reaction. Total and mitochondrial cholesterol content was measured using Amplex Red. To define energy metabolism, we used the Oroboros system in the cells. We report that GRX cells with exogenous expression or knockdown of Cav‐1 changed mitochondrial morphometric parameters, OXPHOS metabolism, ER‐mitochondria distance, lysosomal activity, and may change the activation state of HSC. This study highlights that Cav‐1 may modulate mitochondrial function and structural reorganization in HSC activation, being a potential candidate marker for chronic liver diseases and a molecular target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Hepatic caveolin-1 (CAV1) is reduced in cholesterol gallstone disease (CGD). Mice with CAV1 deficiency were prone to develop CGD. However, it remains unknown whether restored hepatic CAV1 expression prevents the development of CGD. Methods: C57BL/6 mice were injected with adeno-associated virus 2/8 (AAV2/8) vectors carrying the CAV1 gene (AAV2/8CAV1) via intravenous (i.v.) or intraperitoneal (i.p.) route and then subjected to a lithogenic diet (LD) for 8 weeks. Uninjected mice were used as controls. The functional consequences of rescuing CAV1 expression by either i.v. or i.p. AAV2/8CAV1 treatment for CGD prevention and its subsequent molecular mechanisms were examined. Results: CAV1 expression was reduced in the liver and gallbladder of LD-fed CGD mice. We discovered that AAV2/8CAV1 i.p. delivery results in higher transduction efficiency in the gallbladder than tail vein administration. Although either i.v. or i.p. injection of AAV2/8CAV1 improved liver lipid metabolic abnormalities in CGD mice but did not affect LD feeding-induced bile cholesterol supersaturation. In comparison with i.v. administration route, i.p. administration of AAV2/8CAV1 obviously increased CAV1 protein levels in the gallbladder of LD-fed mice, and i.p. delivery of AAV2/8CAV1 partially improved gallbladder cholecystokinin receptor (CCKAR) responsiveness and impeded bile cholesterol nucleation via the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling, which induced a reduction in gallbladder mucin-1 (MUC1) and MUC5ac expression and gallbladder cholesterol accumulation. Conclusion: CGD prevention by i.p. AAV2/8CAV1 injection in LD-fed mice was associated with the improvement of gallbladder stasis, which again supported the notion that supersaturated bile is required but not sufficient for the formation of cholesterol gallstones. Additionally, AAV treatment via the local i.p. injection offers particular advantages over the systemic i.v. route for much more effective gallbladder gene delivery, which will be an excellent tool for conducting preclinical functional studies on the maintenance of normal gallbladder function to prevent CGD. [ABSTRACT FROM AUTHOR]

Objective: Obesity is related to increasing leptin and some inflammatory factors that are associated with low-grade inflammation. Moreover, several studies have shown Caveolin-1 (CAV1) genetic variations may be associated with dietary intake. The current study aimed to evaluate the interaction of CAV1 rs3807992 with types of the energy-adjusted dietary inflammatory index (EDII) in leptin, leptin resistance, and Galectin 3, as inflammatory factors. Methods: This cross-sectional study was carried out on 363 overweight and obese females. Dietary intake and DII were obtained from a 147-item food frequency questionnaire (FFQ). The CAV-1 genotype was measured using the PCR-RFLP method. Anthropometric values and serum levels of leptin and Galectin 3 were measured by standard methods. Results: Increased adherence to EDII in the interaction with CAV1 genotypes led to an increase in leptin level 79.15 (mg/l) (β = 79.15, CI = − 1.23,163.94, P = 0.04) in model 3, after controlling for further potential confounders. By contrast, adherence to EDII in the interaction with the genotype including risk alleles showed no significant interaction, even after adjustment in model 3 (β = 0.55, CI = − 0.99, 2.09, P = 0.48). Although, a marginal positive significant interaction was found between EDII and CAV1 genotypes on Galectin 3, after adjustment in model 3 (β = 31.35, CI = 0.13, 77.13, P = 0.05). Conclusions: The present study indicates that a high adherence of EDII and CAV1 genotypes containing risk alleles may be a prognostic factor and increase both leptin and Galectin3. However, it seems that the presence of interaction was not on leptin resistance. Further functional studies are necessary to elucidate the exact mechanism. [ABSTRACT FROM AUTHOR]

Background: Animal and cell model studies have implicated CAV1 in the pathophysiology of metabolic disorders. Our previous studies demonstrated a potential association of CAV1 rs1997623 C/A variant with pediatric metabolic syndrome (MetS) in Arab children. In the present study, we evaluate whether the CAV1 variant associates with MetS Arab adults as well. The association signal is further examined for ancestry-specific variation by considering cohorts of other ethnicities. Method: The CAV1 rs1997623 was genotyped in three cohorts of Arab (n = 479), South Asian (n = 660), and South East Asian (n = 362) ethnic adults from Kuwait. MetS status of the individuals was diagnosed using the IDF criteria (presence of central obesity and at least two abnormalities out of: elevated TG, low HDL, hypertension, or T2D). The quantitative measure of MetS was calculated as siMS = 2 × WC/Height + FBG/5.6 + TG/1.7 + SBP/130–HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous MetS traits were assessed using linear and logistic regression models adjusted for age and sex. In addition, empirical p-values (Pemp) were generated using max(T) permutation procedure based on 10,000 permutations. Results: The CAV1 variant was significantly associated with MetS status (OR = 1.811 [1.25–2.61]; p-value = 0.0015; Pemp = 0.0013) and with siMS (Effect size = 0.206; p-value = 0.0035; Pemp = 0.0028) in the cohort of Arab individuals. The association was weak and insignificant in the South Asian and South East Asian cohorts (OR = 1.19 and 1.11; p-values = 0.25 and 0.67, respectively). Conclusion: The reported association of CAV1 rs1997623 C/A with MetS in Arab pediatric population is now demonstrated in an adult Arab cohort as well. The weak association signal seen in the Asian cohorts lead us to propose a certain extent of ethnic-specificity in CAV1 rs1997623 association with MetS. [ABSTRACT FROM AUTHOR]

Background: High-altitude cerebral edema (HACE) is a serious and potentially fatal brain injury that is caused by acute hypobaric hypoxia (HH) exposure. Vasogenic edema is the main pathological factor of this condition. Hypoxia-induced disruptions of tight junctions in the endothelium trigger blood‒brain barrier (BBB) damage and induce vasogenic edema. Nuclear respiratory factor 1 (NRF1) acts as a major regulator of hypoxia-induced endothelial cell injury, and caveolin-1 (CAV-1) is upregulated as its downstream gene in hypoxic endothelial cells. This study aimed to investigate whether CAV-1 is involved in HACE progression and the underlying mechanism. Methods: C57BL/6 mice were exposed to HH (7600 m above sea level) for 24 h, and BBB injury was assessed by brain water content, Evans blue staining and FITC-dextran leakage. Immunofluorescence, transmission electron microscope, transendothelial electrical resistance (TEER), transcytosis assays, and western blotting were performed to confirm the role and underlying mechanism of CAV-1 in the disruption of tight junctions and BBB permeability. Mice or bEnd.3 cells were pretreated with MβCD, a specific blocker of CAV-1, and the effect of CAV-1 on claudin-5 internalization under hypoxic conditions was detected by immunofluorescence, western blotting, and TEER. The expression of NRF1 was knocked down, and the regulation of CAV-1 by NRF1 under hypoxic conditions was examined by qPCR, western blotting, and immunofluorescence. Results: The BBB was severely damaged and was accompanied by a significant loss of vascular tight junction proteins in HACE mice. CAV-1 was significantly upregulated in endothelial cells, and claudin-5 explicitly colocalized with CAV-1. During the in vitro experiments, hypoxia increased cell permeability, CAV-1 expression, and claudin-5 internalization and downregulated tight junction proteins. Simultaneously, hypoxia induced the upregulation of CAV-1 by activating NRF1. Blocking CAV-1-mediated intracellular transport improved the integrity of TJs in hypoxic endothelial cells and effectively inhibited the increase in BBB permeability and brain water content in HH animals. Conclusions: Hypoxia upregulated CAV-1 transcription via the activation of NRF1 in endothelial cells, thus inducing the internalization and autophagic degradation of claudin-5. These effects lead to the destruction of the BBB and trigger HACE. Therefore, CAV-1 may be a potential therapeutic target for HACE. E5r9nDKChFa7F_nrUkRwh3 Video abstract [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of miR-192 on proliferation, migration and extracellular matrix of mesangial cells under high glucose condition. Methods Human mesangial cells were cultured in vitro for 24 h and divided into six groups: the normal glucose concentration (NG, 5.6 mmol/L glucose) group, the high glucose concentration (HG, 25 mmol/L glucose) group, the normal glucose concentration+miR-192 mimics (NG+mimics) group, the high glucose concentration+miR-192 mimics (HG+ mimics) group, the normal glucose concentration+miR-192 inhibitor (NG+inhibitor) group and the high glucose concentration+miR-192 inhibitor (HG+inhibitor) group. After 24 h of intervention, cell viability was detected by CCK-8 assay, the cell migration ability was detected by Scratch healing test, and expression levels of miR-192, caveolin 1 (CAV-1), epidermal growth factor (EGF), collagen type 1 (COLⅠ) and fibronectin (FN) mRNA and related proteins were detected by qPCR and Western blot assay. Results Compared with the NG group, the proliferation and migration rates were increased, the expression levels of EGF, FN and COLⅠmRNA and protein were increased, and the expression of CAV-1 mRNA and protein decreased in the HG group (all P＜0.05). When miR-192 inhibitor was added to the NG group and the HG group, the cell proliferation and migration were decreased, the expression of EGF, FN and COLⅠ mRNA and protein were decreased, while the expression levels of CAV-1 mRNA and protein were increased (all P＜0.05). Changes were more significant in the HG group after the addition of miR-192 inhibitor. After adding miR-192 mimics to the NG group and the HG group, the cell proliferation and migration increased, expression levels of EGF, FN and COLⅠ mRNA and protein increased, and the expression of CAV-1 decreased (all P＜0.05). Conclusion High glucose increases the proliferation and migration of glomerular mesangial cells through miR-192-CAV-1-EGF pathway, leading to the formation of extracellular matrix and participating in the occurrence and development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Caveolin-1 (Cav-1) is the basic component of caveolae, a specialized form of lipid raft that plays an essential role in endocytic viral entry. However, the evidence of direct involvement of caveolae and Cav-1 in avian reovirus (ARV) entry remains insufficient. In this study, the membrane lipid rafts were isolated as detergent-resistant microdomains (DRMs) by sucrose gradient centrifugation, and the capsid protein σB of ARV was found to associate with Cav-1 in DRMs fractions. Additionally, the interaction between ARV σB protein and Cav-1 was demonstrated by immunofluorescence co-localization and co-immunoprecipitation assays. Furthermore, we found that the internalization of ARV is sensitive to caveolae and dynamin inhibitors, while it is insensitive to clathrin inhibitors. In conclusion, these results indicate that the ARV σB protein interacts with Cav-1 during dynamin-dependent caveolae-mediated endocytosis for the entry of ARV. [ABSTRACT FROM AUTHOR]

Stem cells have emerged as promising therapeutic options for several human diseases, including pulmonary fibrosis (PF). In this study, we investigated the therapeutic effects of adipose tissuederived mesenchymal stem cells (ADMSCs) in the bleomycininduced PF model rats and the underlying mechanisms. The PF model rats were generated by intratracheal injections of 5 mg/kg bleomycin sulfate. The ADMSC group rats were generated by injecting 2×106 ADMSCs via the tail vein at 0, 12, and 24 h after bleomycin injection. The control, PF, and ADMSC group rats were sacrificed on day 21 after bleomycin injections and the changes in lung histology and the levels of pro-inflammatory cytokines, collagen I, and caveolin-1 (Cav-1), and the activity of the NF-κB signaling pathway in the lung tissues was assessed by hematoxylin-eosin staining, ELISA, and western blotting assays. The lung tissues of the PF model rats showed significant infiltration of neutrophils, tissue destruction, and collagen deposition, but these effects were abrogated by the ADMSCs. The levels of pro-inflammatory cytokines such as IL-6, IL-1β, and TGF-β1 were elevated in the lung tissues and the bronchoalveolar lavage fluid (BALF) of the bleomycin-induced PF model rats, but these effects were reversed by the ADMSCs. The lung tissues of the PF model rats showed significant downregulation of Cav-1 and significantly higher activation of the pro-inflammatory NF-κB pathway. However, administration of the ADMSCs restored the expression levels of Cav-1 and suppressed the NF-κB signaling pathway in the lungs of the bleomycininduced PF model rats. In conclusion, this study demonstrated that the ADMSCs protected against bleomycin-induced PF in the rat model by modulating the Cav-1/NF-κB axis. [ABSTRACT FROM AUTHOR]

Our studies reveal changes in the expression of the main participants in the processing of amyloid precursor protein (APP) in neurons and astrocytes after photothrombotic stroke (PTS). Here we show the increase in the level of N- and C-terminal fragments of APP in the cytoplasm of ischemic penumbra cells at 24 h after PTS and their co-immunoprecipitation with caveolin-1. The ADAM10 α-secretase level decreased in the rat brain cortex on the first day after PTS. Levels of γ-secretase complex proteins presenilin-1 and nicastrin were increased in astrocytes, but not in neurons, in the penumbra after PTS. Inhibitory analysis showed that these changes lead to neuronal death and activation of astrocytes in the early recovery period after PTS. The caveolin-1 inhibitor daidzein shifted APP processing towards Aβ synthesis, which caused astroglial activation. γ-secretase inhibitor DAPT down-regulated glial fibrillary acidic protein (GFAP) in astrocytes, prevented mouse cerebral cortex cells from PTS-induced apoptosis, and reduced the infarction volume. Thus, new generation γ-secretase inhibitors may be considered as potential agents for the treatment of stroke. [ABSTRACT FROM AUTHOR]

Keying Liang, Shengsheng Mei, Xiangzheng Gao, Shanshan Peng, Jinbiao Zhan Department of Biochemistry, Cancer Institute of the Second Affiliated Hospital (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), School of Medicine, Zhejiang University, Hangzhou, 310058, People’s Republic of ChinaCorrespondence: Jinbiao ZhanDepartment of Biochemistry, Cancer Institute of the Second Affiliated Hospital (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, People’s Republic of ChinaTel/Fax +86 571-88208273Email jzhan2k@zju.edu.cnPurpose: T-DM1 is an antibody–drug conjugate (ADC) consisting of trastuzumab and DM1 linked together. T-DM1 binds to human epidermal growth factor receptor-2 (HER2) in tumors and then triggers the endocytosis of T-DM1 and release of payload. Therefore, endocytosis efficacy is considered as a critical step for the initiation of T-DM1 therapy; however, the endocytosis mechanism of T-DM1 remains poorly understood. Meanwhile, HER2 is regarded as an internalization-resistant receptor, which hinders the endocytosis and effectiveness of T-DM1. The present study is to explore the T-DM1 endocytosis pathway, which may provide insights into the internalization mechanism of ADCs and help to improve efficacy.Methods: Confocal microscopy and flow cytometry were used to analyse T-DM1 intracellular trafficking and endocytosis efficiency, while Western blot assay was performed to detect T-DM1 degradation.Results: We found that intracellular T-DM1 was increased to 50% within 12 h. T-DM1 was colocalized with cholera toxin B (CTxB), a lipid raft marker, within 2 h and then degraded in lysosome. Upon overexpression of caveolin-1 (CAV-1) and utilization of caveolae/lipid-raft disruptors, we found that temporal CAV-1 upregulation significantly facilitated T-DM1 endocytosis and degradation, whereas nystatin and lovastatin disrupted caveolae/lipid-raft structure and inhibited T-DM1 degradation. We demonstrate that T-DM1 internalizes through the lipid raft-mediated endocytosis in a CAV-1 dependent manner, rather than through the clathrin-mediated endocytosis in HER2-positive cancer cells.Conclusion: Our findings suggest that modulation of the caveolae/lipid-raft mediated endocytosis may be a possible option for improving the clinical therapeutic effect of T-DM1 because it plays a key role in regulating T-DM1 internalization.Keywords: antibody–drug conjugate, T-DM1, endocytosis, lipid rafts, caveolae, caveolin-1

Abstract Background DLC1, a tumor suppressor gene that is downregulated in many cancer types by genetic and nongenetic mechanisms, encodes a protein whose RhoGAP and scaffolding activities contribute to its tumor suppressor functions. The role of the DLC1 START (StAR-related lipid transfer; DLC1-START) domain, other than its binding to Caveolin-1, is poorly understood. In other START domains, a key function is that they bind lipids, but the putative lipid ligand for DLC1-START is unknown. Methods Lipid overlay assays and Phosphatidylserine (PS)-pull down assays confirmed the binding of DLC1-START to PS. Co-immunoprecipitation studies demonstrated the interaction between DLC1-START and Phospholipase C delta 1 (PLCD1) or Caveolin-1, and the contribution of PS to those interactions. Rho-GTP, cell proliferation, cell migration, and/or anchorage-independent growth assays were used to investigate the contribution of PS and PLCD1, or the implications of TCGA cancer-associated DLC1-START mutants, to DLC1 functions. Co-immunoprecipitations and PS-pull down assays were used to investigate the molecular mechanisms underlying the impaired functions of DLC1-START mutants. A structural model of DLC1-START was also built to better understand the structural implications of the cancer-associated mutations in DLC1-START. Results We identified PS as the lipid ligand for DLC1-START and determined that DLC1-START also binds PLCD1 protein in addition to Caveolin-1. PS binding contributes to the interaction of DLC1 with Caveolin-1 and with PLCD1. The importance of these activities for tumorigenesis is supported by our analysis of 7 cancer-associated DLC1-START mutants, each of which has reduced tumor suppressor function but retains wildtype RhoGAP activity. Our structural model of DLC1-START indicates the mutants perturb different elements within the structure, which is correlated with our experimental findings that the mutants are heterogenous with regard to the deficiency of their binding properties. Some have reduced PS binding, others reduced PLCD1 and Caveolin-1 binding, and others are deficient for all of these properties. Conclusion These observations highlight the importance of DLC1-START for the tumor suppressor function of DLC1 that is RhoGAP-independent. They also expand the versatility of START domains, as DLC1-START is the first found to bind PS, which promotes the binding to other proteins.

Caveolae, the specialized cell-surface plasma membrane invaginations which are abundant in endothelial cells, play critical roles in regulating various cellular processes, including cholesterol homeostasis, nitric oxide production, and signal transduction. Endothelial caveolae serve as a membrane platform for compartmentalization, modulation, and integration of signal events associated with endothelial nitric oxide synthase, ATP synthase β, and integrins, which are involved in the regulation of endothelial dysfunction and related cardiovascular diseases, such as atherosclerosis and hypertension. Furthermore, these dynamic microdomains on cell membrane are modulated by various extracellular stimuli, including cholesterol and flow shear stress. In this brief review, we summarize the critical roles of caveolae in the orchestration of endothelial function based on recent findings as well as our work over the past two decades.

Migration of cancer cells leads to the invasion of distant organs by primary tumors. Further, endogenous electric fields (EFs) in the tumor microenvironment direct the migration of lung cancer cells by a process referred to as electrotaxis - although the precise mechanism remains unclear. Caveolin-1 (Cav-1) is a multifunctional scaffolding protein that is associated with directional cell migration and lung cancer invasion; however, its precise role in lung cancer electrotaxis is unknown. In the present study, we first detected outward electric currents on the tumor body surface in lung cancer xenografts using a highly-sensitive vibrating probe. Next, we found that highly-metastatic H1650-M3 cells migrated directionally to the cathode. In addition, reversal of the EF polarity reversed the direction of migration. Mechanistically, EFs activated Cav-1 and the downstream signaling molecule STAT3. RNA interference of Cav-1 reduced directional cell migration, which was accompanied by dampened STAT3 activation. Furthermore, pharmacological inhibition of STAT3 significantly reduced the electrotactic response, while rescue of STAT3 activation in Cav-1 knock-down cells restored electrotaxis. Taken together, these results suggest that endogenous EFs in the tumor micro-environment might play an important role in lung cancer metastasis by guiding cell migration through a Cav-1/STAT3-mediated signaling pathway.

BackgroundThe pathophysiology of increased severity of erectile dysfunction in men with diabetes and their poor response to oral pharmacotherapy are unclear. Defective vascular endothelium and consequent impairment in the formation and action of nitric oxide (NO) are implicated as potential mechanisms. Endothelial NO synthase, critical for NO generation, is localized to caveolae, plasma membrane lipid rafts enriched in structural proteins, and caveolins. Type 2 diabetes mellitus (T2DM)-induced changes in caveolin expression are recognized to play a role in cardiovascular dysfunction.AimsTo evaluate DM-related changes to male erectile tissue in a mouse model that closely resembles human T2DM and study the specific role of caveolins in penile blood flow and microvascular perfusion using mice lacking caveolin (Cav)-1 or Cav-3.MethodsWe used wild-type C57BL6 (control) and Cav-1 and Cav-3 knockout (KO) male mice. T2DM was induced by streptozotocin followed by a high-fat diet for 4 months. Penile expressions of Cav-1, Cav-3, and endothelial NO synthase were determined by western blot, and phosphodiesterase type 5 activity was measured using [3H] cyclic guanosine monophosphate as a substrate. For hemodynamic studies, Cav-1 and Cav-3 KO mice were anesthetized, and penile blood flow (peak systolic velocity and end-diastolic velocity; millimeters per second) was determined using a high-frequency and high-resolution digital imaging color Doppler system. Penile tissue microcirculatory blood perfusion (arbitrary perfusion units) was measured using a novel PeriCam PSI system.OutcomesPenile erectile tissues were harvested for histologic studies to assess Cav-1, Cav-3, and endothelial NO synthase expression, phosphodiesterase type 5 activity, and blood flow, and perfusion measurements were assessed for hemodynamic studies before and after an intracavernosal injection of prostaglandin E1 (50 ng).ResultsIn T2DM mice, decreased Cav-1 and Cav-3 penile protein expression and increased phosphodiesterase type 5 activity were observed. Decreased response to prostaglandin E1 in peak systolic velocity (33 ± 4 mm/s in Cav-1 KO mice vs 62 ± 5 mm/s in control mice) and perfusion (146 ± 12 AU in Cav-1 KO mice vs 256 ± 12 AU in control mice) was observed. Hemodynamic changes in Cav-3 KO mice were insignificant.Clinical translationOur findings provide novel mechanistic insights into erectile dysfunction severity and poor pharmacotherapy that could have potential application to patients with T2DM.Strengths and limitationsUse of KO mice and novel hemodynamic techniques are the strengths. A limitation is the lack of direct evaluation of penile hemodynamics in T2DM mice.ConclusionAltered penile Cav-1 expression in T2DM mice and impaired penile hemodynamics in Cav-1 KO mice suggests a regulatory role for Cav-1 in DM-related erectile dysfunction. Parikh J, Zemljic-Harpf A, Fu J, et al. Altered Penile Caveolin Expression in Diabetes: Potential Role in Erectile Dysfunction. J Sex Med 2017;14:1177-1186.

Caveolin-1 is a major component protein of the caveolae-a type of flask shaped, 50-100 nm, nonclathrin-coated, microdomain present in the plasma membrane of most mammalian cells. Caveolin-1 functions as a scaffolding protein to organize and concentrate signaling molecules within the caveolae, which may be associated with its unique physicochemical properties including oligomerization, acquisition of detergent insolubility, and association with cholesterol. Here we demonstrate that caveolin-1 is detected in all brain areas examined and recovered in both detergent-soluble and -insoluble fractions. Surprisingly, the recovered molecules from the two different fractions share a similar molecular size ranging from 200 to 2,000 kDa, indicated by gel filtration. Furthermore, both soluble and insoluble caveolin-1 molecules generate a proteinase K (PK)-resistant C-terminal core fragment upon the PK-treatment, by removing ˜36 amino acids from the N-terminus of the protein. Although it recognizes caveolin-1 from A431 cell lysate, an antibody against the C-terminus of caveolin-1 fails to detect the brain protein by Western blotting, suggesting that the epitope in the brain caveolin-1 is concealed. No significant differences in the physicochemical properties of caveolin-1 between uninfected and prion-infected brains are observed.

Background: Animal and cell model studies have implicated CAV1 in the pathophysiology of metabolic disorders. Our previous studies demonstrated a potential association of CAV1 rs1997623 C/A variant with pediatric metabolic syndrome (MetS) in Arab children. In the present study, we evaluate whether the CAV1 variant associates with MetS Arab adults as well. The association signal is further examined for ancestry-specific variation by considering cohorts of other ethnicities.Method: The CAV1 rs1997623 was genotyped in three cohorts of Arab (n = 479), South Asian (n = 660), and South East Asian (n = 362) ethnic adults from Kuwait. MetS status of the individuals was diagnosed using the IDF criteria (presence of central obesity and at least two abnormalities out of: elevated TG, low HDL, hypertension, or T2D). The quantitative measure of MetS was calculated as siMS = 2 × WC/Height + FBG/5.6 + TG/1.7 + SBP/130–HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous MetS traits were assessed using linear and logistic regression models adjusted for age and sex. In addition, empirical p-values (Pemp) were generated using max(T) permutation procedure based on 10,000 permutations.Results: The CAV1 variant was significantly associated with MetS status (OR = 1.811 [1.25–2.61]; p-value = 0.0015; Pemp = 0.0013) and with siMS (Effect size = 0.206; p-value = 0.0035; Pemp = 0.0028) in the cohort of Arab individuals. The association was weak and insignificant in the South Asian and South East Asian cohorts (OR = 1.19 and 1.11; p-values = 0.25 and 0.67, respectively).Conclusion: The reported association of CAV1 rs1997623 C/A with MetS in Arab pediatric population is now demonstrated in an adult Arab cohort as well. The weak association signal seen in the Asian cohorts lead us to propose a certain extent of ethnic-specificity in CAV1 rs1997623 association with MetS.

Summary: Background: Thrombo-inflammation is an important checkpoint that orchestrates infarct development in ischemic stroke. However, the underlying mechanism remains largely unknown. Here, we explored the role of endothelial Caveolin-1 (Cav-1) in cerebral thrombo-inflammation. Methods: The correlation between serum Cav-1 level and clinical outcome was analyzed in acute ischemic stroke patients with successful recanalization. Genetic manipulations by endothelial-specific adeno-associated virus (AAV) and siRNA were applied to investigate the effects of Cav-1 in thrombo-inflammation in a transient middle cerebral artery occlusion (tMCAO) model. Thrombo-inflammation was analyzed by microthrombosis formation, myeloid cell infiltration, and endothelial expression of adhesion molecules as well as inflammatory factors. Findings: Reduced circulating Cav-1, with the potential to predict microembolic signals, was more frequently detected in recanalized stroke patients without early neurological improvement. At 24 h after tMCAO, serum Cav-1 was consistently reduced in mice. Endothelial Cav-1 was decreased in the peri-infarct region. Cav-1−/− endothelium, with prominent barrier disruption, displayed extensive microthrombosis, accompanied by increased myeloid cell inflammatory infiltration after tMCAO. Specific enhanced expression of endothelial Cav-1 by AAV-Tie1-Cav-1 remarkably reduced infarct volume, attenuated vascular hyper-permeability and alleviated thrombo-inflammation in both wild-type and Cav-1−/− tMCAO mice. Transcriptome analysis after tMCAO further designated Rxrg as the most significantly changed molecule resulting from the knockdown of Cav-1. Supplementation of RXR-γ siRNA reversed AAV-Tie1-Cav-1-induced amelioration of thrombo-inflammation without affecting endothelial tight junction. Interpretation: Endothelial Cav-1/RXR-γ may regulate infarct volume and neurological impairment, possibly through selectively controlling thrombo-inflammation coupling, in cerebral ischemia/reperfusion. Funding: This work was supported by National Natural Science Foundation of China.

In recent years, human serum albumin (HSA) has been characterized as an ideal drug carrier in the cancer arena. Caveolin-1 (Cav-1) has been established as the principal structural protein of caveolae and, thus, critical for caveolae-mediated endocytosis. Cav-1 has been shown to be overexpressed in cancers of the lung and pancreas, among others. We found that Cav-1 expression plays a critical role in both HSA uptake and response to albumin-based chemotherapies. As such, developing a novel albumin-based chemotherapy that is more selective for tumors with high Cav-1 expression or high levels of caveolar-endocytosis could have significant implications in biomarker-directed therapy. Herein, we present the development of a novel and effective HSA-SN-38 conjugate (SSH20). We find that SSH20 uptake decreases significantly by immunofluorescence assays and western blotting after silencing of Cav-1 expression through RNA interference. Decreased drug sensitivity occurs in Cav-1-depleted cells using cytotoxicity assays. Importantly, we find significantly reduced sensitivity to SSH20 in Cav-1-silenced tumors compared to Cav-1-expressing tumors in vivo. Notably, we show that SSH20 is significantly more potent than irinotecan in vitro and in vivo. Together, we have developed a novel HSA-conjugated chemotherapy that is potent, effective, safe, and demonstrates improved efficacy in high Cav-1-expressing tumors.

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

Abstract Background Metabolic syndrome (MetS) is associated with an increased risk of morbidity and mortality in almost all chronic diseases. The most frequent methods for the calculation of a continuous MetS (cMetS) score have used the standardized residuals in linear regression (z-score). Recently, emerging data suggest that one of the main genetic targets is the CAV1, which plays a crucial role in regulating body fat distribution. This study is designed to investigate the relationship between CAV1 rs3807992 genotypes and cMetS, and to determine whether body fat distribution plays a mediating role in this regard. Methods The current cross-sectional study was conducted on 386 overweight and obese females. The CAV1 rs3807992 and body composition were measured by the PCR–RFLP method and bioelectrical impedance analysis, respectively. Serum profile of HDL-C, TGs, FPG, and Insulin were measured by standard protocols. Results GG allele carriers had significantly lowered Z-MAP (p = 0.02), total cMetS (p = 0.03) and higher Z-HDL (p = 0.001) compared with (A) allele carriers. There was a significant specific indirect effect (standardized coefficient = 0.19; 95% CI 0.01–0.4) of Visceral fat level (VFL). Although, total body fat was significantly associated with CAV1 rs3807992 and cMetS, the specific indirect effect was not significant (standardized coefficient = 0.21; 95% CI − 0.006, 0.44). VFL contributed to significant indirect effects of 35% on the relationship between CAV1 and cMetS. Conclusion Higher visceral adipose tissue may affect the relationship between CAV1 and cMetS. Although CAV1 rs3807992 is linked to VFL in our study, the influence of this polymorphism on MetS is not via total fat.

Abstract Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

Abstract Background Caveolin-1 (CAV-1) is a cholesterol-dependent essential component located in caveolae. Several studies have been CAV-1 related to cardio-metabolic parameters in animal models, however, there are few studies in humans. Importantly, there is no study has investigated the interaction between CAV-1 rs3807992 gene and dietary patterns (DPs) on cardio-metabolic risk factors. Methods The current cross-sectional study was conducted on 404 overweight and obese women. Dietary intake was obtained from FFQ with 147 items. The CAV-1 genotype was measured by the PCR-RFLP method. The anthropometric measurements, serum lipid profile, and inflammatory markers were measured by standard protocols. Results There was a significant interaction between CAV-1 rs3807992 and healthy DP on high-density cholesterol (HDL) (P-interaction = 0.03), TC/HDL (P-interaction = 0.03) and high sensitivity C-reactive protein (hs-CRP) (P-interaction = 0.04); in A-allele carriers, higher following a healthy DP was related to a higher level of HDL and lower TC/HDL and hs-CRP. As well as, the significant interactions were observed between CAV-1 rs3807992 and unhealthy DP in relation to triglyceride (TG) (P-interaction = 0.001), aspartate aminotransferase (AST) (P-interaction = 0.01) and monocyte chemoattractant protein-1(MCP-1) (P-interaction = 0.01); A-allele carriers were more following the unhealthy DP had lower levels of TG, AST and MCP-1. Conclusions Our study revealed a significant gene-diet interaction between rs3807992 SNPs and DPs in relation to cardio-metabolic risk factors; A-allele carriers might be more sensitive to dietary composition compared to GG homozygotes. Following a healthy DP in A-allele-carriers may be improved their genetic association with cardio-metabolic risk factors.

[Display omitted] Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, with a complex and contentious pathogenesis. Caveolin-1 (CAV1) is an important regulator of liver function and can mitigate liver injury by scavenging reactive oxygen species (ROS). Evidence suggests that NOX4 is a source of ROS production, that oxidative stress and ferroptosis are closely related, and that both are involved in the onset and progression of NAFLD. However, whether CAV1 attenuates liver injury in NAFLD caused by high-fat diet via the NOX4/ROS/GPX4 pathway remains unclear. An in vivo fatty liver model was established by feeding mice with a high-fat diet for 16 weeks. In addition, an in vitro fatty liver model was established by incubating AML-12 cells with free fatty acids for 24 h using an in vitro culture method. In our study, it was observed that a high-fat diet induces mitochondrial damage and worsens oxidative stress in NAFLD. This diet also hinders GPX4 expression, leading to an escalation of ferroptosis and lipid accumulation. To counteract these effects, intraperitoneal administration of CSD peptide in mice attenuated the high-fat diet-induced liver mitochondrial damage and ferroptosis. Likewise, overexpression of CAV1 resulted in an increase in GPX4 expression and a reduction in levels of ROS-mediated iron metamorphosis, thus mitigating the progression of the disease. However, the effects of CAV1 on GPX4-mediated ferroptosis and lipid deposition could be reversed by CAV1 small interfering RNA (SiRNA). Finally, NOX4 inhibitor (GLX351322) treatment increased CAV1 siRNA-mediated GPX4 expression and decreased the level of ROS-mediated ferroptosis. These findings suggest a potential mechanism underlying the protective role of CAV1 against high-fat diet-induced hepatotoxicity in NAFLD, shedding new light on the interplay between CAV1, GPX4, and ferroptosis in liver pathology. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) releases anti-contractile bioactive molecules including NO. PVAT anti-contractile activity is attenuated in mice lacking AMPKα1 (AMP-activated protein kinase-α1). As AMPK regulates endothelial NO synthase (eNOS) activity in cultured cells, NO synthesis was examined in PVAT from AMPKα1 knockout (KO) mice. Endothelium-denuded thoracic or abdominal aortic rings were isolated from wild type (WT) and KO mice. NOS inhibition enhanced vasoconstriction in PVAT-intact thoracic aortic rings from mice of either genotype yet had no effect on abdominal rings as assessed by wire myography. Thoracic aorta PVAT exhibited increased NO production, NOS activity and levels of the brown adipose tissue marker uncoupling protein-1 (UCP1) compared to abdominal PVAT. In KO mice, NO production was significantly reduced in thoracic but not abdominal PVAT. Reduced NO production in KO thoracic PVAT was not due to altered levels or phosphorylation of eNOS but was associated with increased caveolin-1:eNOS association and caveolin-1 Tyr14 phosphorylation. A peptide that disrupts eNOS:caveolin-1 association increased NO synthesis and reduced vasoconstriction of PVAT-intact thoracic but not abdominal aortic rings. KO thoracic PVAT also exhibited reduced UCP1 levels. Murine thoracic aorta PVAT exhibits higher NO synthesis and UCP1 levels than abdominal aortic PVAT. Downregulation of AMPK suppresses NO synthesis which may contribute to the reduced anticontractile activity and reduced brown adipose tissue phenotype of KO thoracic PVAT. The mechanism underlying the effect of AMPK downregulation likely results from increased caveolin-1:eNOS association associated with caveolin-1 Tyr14 phosphorylation. [Display omitted] [ABSTRACT FROM AUTHOR]

The modified cell-penetrating peptide Pas2r12 can deliver antibodies (IgG, 150 kDa) and enhanced green fluorescent protein (EGFP1, 27 kDa) into the cytosol through caveolae-dependent endocytosis. In this study, we determined the effect of Caveolin-1 overexpression on the cytosolic delivery of EGFP by Pas2r12. Three types of Caveolin-1 overexpressing strains were isolated, including Cav1L (low), Cav1M (medium), and Cav1H (high), using HEK293 as the parent cell line. We found that the number of caveolae on the surface of the Caveolin-1-overexpressing strains was similar to that of HEK293. We examined the cytosolic delivery rate of EGFP by Pas2r12. In the Cav1L and Cav1M cells, there was little change compared with HEK293; however, in Cav1H, the rate was significantly decreased. Moreover, the amount of EGFP uptake into the cells (total intracellular EGFP) showed an increasing trend in Cav1H compared with HEK293. These results indicate that in Cav1H, the amount of EGFP uptake into the cells increases, whereas the cytosolic delivery rate of EGFP decreases. This suggests that high overexpression of Caveolin-1 inhibits the transition of EGFP from endosomes to the cytosol. [Display omitted] • Overexpression of Caveolin-1 in HEK293 cells does not significantly alter caveolae numbers. • In Caveolin-1 overexpressing cells, Pas2r12 increases the total intracellular uptake of EGFP. • In cells with high Caveolin-1 overexpression, Pas2r12-mediated cytosolic transfer of EGFP is inhibited. [ABSTRACT FROM AUTHOR]

The main symptom of acute glaucoma is acute ocular hypertension (AOH), which leads to the death of retinal ganglion cells (RGCs) and permanent loss of vision. However, effective treatments for these conditions are lacking. This study aimed to identify major regulators and overall protein changes involved in AOH-induced RGC death. Proteomic patterns of the retinal protein extracts from the AOH and sham groups were analyzed using mass spectrometry (MS), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Proteomic analysis revealed 92 proteins in the AOH group compared to the control group; 58 proteins were upregulated and 34 were downregulated. Alterations in fatty acid-binding protein 7 (FABP7) and caveolin-1 (Cav-1), which are related to fatty acid metabolism and ocular inflammatory signaling, were detected using western blotting and biochemical assays. Variations in the expression of galectin-1 (Gal-1), S100 calcium-binding protein A6 (S100a6), and visinin-like protein-1 (VILIP) have been associated with neuronal ischemia. Our investigation demonstrates that neuroinflammation and fatty acid metabolism are involved in retinal impairment following AOH, suggesting a possible treatment approach for acute glaucoma. • Neuroinflammation and the metabolism of fatty acids were identified as factors potentially contributing to retinal damage after I/R injury. • In response to retinal ischemia/reperfusion (I/R) injury, there appears to be an upregulation of FABP7 and Cav-1 expression in the retina. • The interaction between FABP7 and Caveolin-1 in the PPAR/JAK-STAT signaling pathway could contribute to retinal neuronal cell death caused by retinal I/R injury. [ABSTRACT FROM AUTHOR]

Glaucoma is a degenerative disease characterized by retinal ganglion cell (RGC) death and visual impairment caused by elevated intraocular pressure (IOP). Elevated IOP can activate microglia, which participate in ganglion cell injury. Based on the study of caveolin-1 (Cav-1) in glaucoma, we aimed to explore the effect and mechanism of Cav-1 on RGC apoptosis in mice with acute ocular hypertension (AOH). AOH mice were established, and Cav-1 was intravitreally injected. Retinal microglia and RGCs were isolated from neonatal mice. TUNEL staining, hematoxylin-eosin staining, immunohistochemistry, flow cytometry, PCR and western blotting were used to observe the effect of Cav-1 on RGCs and mouse retinas. The thickness of the whole retina and the inner retinal sublayer decreased significantly, retinal cell apoptosis increased after AOH injury, and Cav-1 treatment reversed the effect of AOH injury. In addition, Cav-1 treatment promoted the conversion of proinflammatory M1 microglia to anti-inflammatory M2 microglia. Microglia and RGCs were isolated from neonatal mice. Cav-1 protects RGCs from OGD/R-induced injury by changing the polarization status of retinal microglia in vitro. Further studies revealed that Cav-1 activated the Akt/PTEN signaling pathway and inhibited TLR4. Our study provides evidence that Cav-1 may be a promising therapeutic target for glaucoma. [ABSTRACT FROM AUTHOR]

DCBLD2 is a neuropilin‐like transmembrane protein that is up‐regulated during arterial remodeling in humans, rats, and mice. Activation of PDGFR‐β via PDGF triggers receptor phosphorylation and endocytosis. Subsequent activation of downstream signals leads to the stimulation of phenotypic conversion of VSMCs and arterial wall proliferation, which are common pathological changes in vascular remodeling diseases such as atherosclerosis, hypertension, and restenosis after angioplasty. In this study, we hypothesized that DCBLD2 regulates neointimal hyperplasia through the regulation of PDGFR‐β endocytosis of vascular smooth muscle cells (VSMCs) through Caveolin‐1 (Cav‐1). Compared with wild‐type (WT) mice or control littermate mice, the germline or VSMC conditional deletion of the Dcbld2 gene resulted in a significant increase in the thickness of the tunica media in the carotid artery ligation. To elucidate the underlying molecular mechanisms, VSMCs were isolated from the aorta of WT or Dcbld2−/− mice and were stimulated with PDGF. Western blotting assays demonstrated that Dcbld2 deletion increased the PDGF signaling pathway. Biotin labeling test and membrane‐cytosol separation test showed that after DCBLD2 was knocked down or knocked out, the level of PDGFR‐β on the cell membrane was significantly reduced, while the amount of PDGFR‐β in the cytoplasm increased. Co‐immunoprecipitation experiments showed that after DCBLD2 gene knock‐out, the binding of PDGFR‐β and Cav‐1 in the cytoplasm significantly increased. Double immunofluorescence staining showed that PDGFR‐β accumulated Cav‐1/lysosomes earlier than for control cells, which indicated that DCBLD2 gene knock‐down or deletion accelerated the endocytosis of PDGF‐induced PDGFR‐β in VSMCs. In order to confirm that DCBLD2 affects the relationship between Cav‐1 and PDGFR‐β, proteins extracted from VSMCs cultured in vitro were derived from WT and Dcbld2−/− mice, whereas co‐immunoprecipitation suggested that the combination of DCBLD2 and Cav‐1 reduced the bond between Cav‐1 and PDGFR‐β, and DCBLD2 knock‐out was able to enhance the interaction between Cav‐1 and PDGFR‐β. Therefore, the current results suggest that DCBLD2 may inhibit the caveolae‐dependent endocytosis of PDGFR‐β by anchoring the receptor on the cell membrane. Based on its ability to regulate the activity of PDGFR‐β, DCBLD2 may be a novel therapeutic target for the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The engagement of cadherins, cell-to-cell adhesion proteins, triggers a dramatic increase in the levels and activity of the Rac/Cdc42 GTPases, through the inhibition of proteasomal degradation. This leads to an increase in transcription and secretion of IL6 family cytokines, activation of their common receptor, gp130, in an autocrine manner and phosphorylation of the signal transducer and activator of transcription-3 (Stat3) on tyrosine-705 by the Jak kinases. Stat3 subsequently dimerizes, migrates to the nucleus and activates the transcription of genes involved in cell division and survival. The Src oncogene also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers a Stat3-ptyr705 increase. Interestingly, at the same time, Src downregulates cadherins in a quantitative manner, while cadherins are required to preserve gp130 levels for IL6 family signalling. Therefore, a fine balance between Src527F/Rac/IL6 and Src527F/cadherin/gp130 levels is in existence, which is required for Stat3 activation. This further demonstrates the important role of cadherins in the activation of Stat3, through preservation of gp130 function. Conversely, the absence of cadherin engagement correlates with low Stat3 activity: In sparsely growing cells, both gp130 and Stat3-ptyr705 levels are very low, despite the fact that cSrc is active in the FAK (focal adhesion kinase)/cSrc complex, which further indicates that the engagement of cadherins is important for Stat3 activation, not just their presence. Furthermore, the caveolin-1 protein downregulates Stat3 through binding and sequestration of cadherins to the scaffolding domain of caveolin-1. We hypothesize that the cadherins/Rac/gp130 axis may be a conserved pathway to Stat3 activation in a number of systems. This fact could have significant implications in Stat3 biology, as well as in drug testing and development. [ABSTRACT FROM AUTHOR]

The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2+) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2+ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+ Cav-1High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+ Cav-1High cells but not in HER2+ Cav-1Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)- Lova(D2)-Lova & Tras(D2 + 12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+ Cav-1High tumors, which might be a promising combination regimen for these patients in clinics. [ABSTRACT FROM AUTHOR]

Monocytes and macrophages are implicated in inflammation and atherosclerosis, whereas monocytes are involved in psoriasis lesion formation. We previously reported a psoriatic inflammation-associated significant decrease in the membrane protein caveolin-1 (CAV-1) in psoriasis patient monocytes. However, the phenotype of circulating monocytes and their macrophage differentiation in psoriasis patients remain unclear. We sought to clarify circulating monocyte and monocyte-derived macrophage (MDM) phenotypes in psoriasis patients with and without comorbidities. Thirty-one patients with psoriasis vulgaris and 28 control subjects were included. Surface macrophage markers and inflammatory status were examined in circulating monocytes and MDMs from both groups. Expression of CD36, which mediates macrophage uptake of oxidized low-density lipoprotein (oxLDL), was evaluated in these cells. CAV-1 -silenced monocytes were differentiated into macrophages to investigate the effects of CAV-1 downregulation on psoriatic inflammation and atherosclerosis. Macrophage surface markers were detectable in circulating monocytes. A significant M1 shift was detected in monocytes and MDMs in psoriasis patients, including those without cardiovascular disease risk factors, as compared to controls. MDMs of psoriasis patients had more CD36-expressing cells, which are associated with atherosclerosis risk. Additionally, CAV-1 -silencing in monocytes increased the likelihood of M1-biased macrophage differentiation and increased pro-inflammatory cytokine production. Monocytes from psoriasis patients were more likely to differentiate into M1-dominant macrophages, correlating with inflammatory status and CAV-1 expression. These aberrant inflammatory monocytes not only contribute to psoriatic inflammation by producing psoriatic cytokines, but also have a phenotype that could increase atherosclerosis risk by uptake of oxLDL and formation of foam cells. • Circulating monocytes and monocyte-derived macrophages from psoriasis patients showed a M1-biased phenotype. • Macrophages expressing CD36, a receptor that mediates macrophage uptake of oxLDL, are increased in psoriasis patients. • Caveolin-1-reduced monocytes may affect macrophage differentiation and might relate to inflammation and comorbidities.. • Monocyte/macrophage exhibited a phenotype related to not only psoriatic inflammation, but a possible risk for atherosclerosis. [ABSTRACT FROM AUTHOR]

Extracellular vesicles are recognized as signaling mediators between cells both in physiological and pathological communication. In this work, we explored the potential effect of citicoline to modify relevant proteins or miRNAs for cardioprotection in the smallest population of such microvesicles; i.e., in exosomes from patients diagnosed with ST-segment elevation myocardial infarction (STEMI) undergoing coronary angioplasty. The plasma-exosome-enriched fraction from these patients was characterized. Their cellular origin was assessed by flow cytometry and Western blot, whereas miRNA expression was evaluated by real-time polymerase chain reaction (qRT-PCR). The content of caveolin-1, caveolin-3, and hnRNPA2B1, which play a relevant role in selective transport of miRNAs into microvesicles, along with the effect on cell viability of the exosomes obtained from citicoline-treated and untreated groups were also analyzed. Our results showed that hypoxic stress increases exosome release into the circulation. Moreover, we found that CD146+ increased in exosomes from citicoline-treated patients, while CD142+ decreased in these patients compared to the placebo group. No changes were detected in the protein levels of caveolin-1, caveolin-3, and hnRNPA2B1. Citicoline administration modified the expression of miR233-3p, miR92, and miR21-5p in exosomes. Cell viability decreased in the presence of exosomes from infarcted patients, while incubation of H9c2 cells with exosomes from patients reperfused with citicoline did not affect cell viability. In conclusion, citicoline administration modifies the expression of specific miRNAs related to cardioprotection in exosomes. [ABSTRACT FROM AUTHOR]

Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of Streptococcus pneumonia, a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca2+ levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol. We hypothesized that the abundance of cholesterol-rich domains in EC plasma membranes confers cellular susceptibility to PLY. Contrary to this hypothesis, we found increased PLY-induced IC Ca2+ following membrane cholesterol depletion. Caveolin-1 (Cav-1) is an essential structural protein of caveolae and its regulation by cholesterol levels suggested a possible role in EC barrier function. Indeed, Cav-1 and its scaffolding domain peptide protected the endothelial barrier from PLY-induced disruption. In loss of function experiments, Cav-1 was knocked-out using CRISPR-Cas9 or silenced in human lung microvascular ECs. Loss of Cav-1 significantly enhanced the ability of PLY to disrupt endothelial barrier integrity. Rescue experiments with re-expression of Cav-1 or its scaffolding domain peptide protected the EC barrier against PLY-induced barrier disruption. Dynamin-2 (DNM2) is known to regulate caveolar membrane endocytosis. Inhibition of endocytosis, with dynamin inhibitors or siDNM2 amplified PLY induced EC barrier dysfunction. These results suggest that Cav-1 protects the endothelial barrier against PLY by promoting endocytosis of damaged membrane, thus reducing calcium entry and PLY-dependent signaling. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment. [ABSTRACT FROM AUTHOR]

Background: The fluctuation in serum caveolin-1 (Cav-1) concentrations is an important indicator of many diseases. Irrespective of the actual cause, a significant reduction of serum Cav-1 is associated with a significant increase in insulin secretion and hyperinsulinemia. The aim of the current study was to evaluate the relationship between serum Cav-1, serum vaspin and visfatin in newly diagnosed men with T2DM. Methods: Eighty-two newly diagnosed men with T2DM were matched for age and body mass indexes (BMIs) with a similar number of non-diabetic men. Serum Cav-1, vaspin and visfatin were assessed through enzyme-linked immunosorbent assay. Fasting serum glucose (FSG), glycohaemoglobin A1C (HbA1c) were both measured using automated method. In addition, waist-circumferences, waist-hip ratio, systolic (SBP), and diastolic blood pressure (DBP) were also obtained. Results: Serum concentration of Cav-1(ng/mL) was significantly low in men newly diagnosed with T2DM, (2.334±0.7627) compared with non-diabetic controls (4.321±1.143), p< 0.0001. In contrast, patients with T2DM exhibited significantly higher serum concentrations of vaspin and visfatin (ng/mL), 142.4±60.53) and 2.99±1.091), than controls, 81.53±39.32) and 1.456±0.654), respectively, p< 0.0001. Expectedly, patients with T2DM have significantly higher FSG, HbA1c, systolic blood pressure (SBP), and diastolic blood pressure (DBP). Conclusions: There was an inverse significant relationship between Cav-1 and vaspin, visfatin, HbA1c, FSG, and hypertension. This study suggests that serum Cav-1 can be used as a diagnostic marker to predict T2DM in individuals and families under high risk. [ABSTRACT FROM AUTHOR]

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Purpose Adenosine monophosphate-activated protein kinase (AMPK) is thought to inhibit cell proliferation or promote cell death, but the details remain unclear. In this study, we propose that AMPK inhibits the expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) by relying on the hypoxia-inducible factor 1 alpha (HIF-1α)-induced caveolin-1 (Cav-1) expression pathway in noninvasive human bladder tumor (RT4) cells. Methods In cells exposed to a hypoxic environment (0.5% oxygen), the levels of expression and phospho-activity of the relevant signaling enzymes were examined via Western blots and reverse transcription-polymerase chain reaction. Cell proliferation was assessed using a Cell Counting Kit-8 assay. Results The level of expression of Cav-1 was very low or undetectable in RT4 cells. Hypoxia was associated with significantly decreased cell growth, along with marked induction of HIF-1α and Cav-1 expression; additionally, it suppressed the expression of the antiapoptotic marker Bcl-2 while leaving AMPK activity unchanged. Under hypoxic conditions, HIF-1α acts as a transcription factor for Cav-1 mRNA gene expression. The cell growth and Bcl-2 expression suppressed under hypoxia were reversed along with decreases in the induced HIF-1α and Cav-1 levels by AMPK activation with metformin (1mM) or phenformin (0.1mM). In addition, pretreatment with AMPK small interfering RNA not only increased the hypoxia-induced expression of HIF-1α and Cav-1, but also reversed the suppression of Bcl-2 expression. These results suggest that HIF-1α and Cav-1 expression in hypoxic environments is regulated by basal AMPK activity; therefore, the inhibition of Bcl-2 expression cannot be expected when AMPK activity is suppressed, even if Cav-1 expression is elevated. Conclusions For the first time, we find that AMPK activation can regulate HIF-1α induction as well as HIF-1α-induced Cav1 expression, and the hypoxia-induced inhibitory effect on the antiapoptotic pathway in RT4 cells is due to Cav-1-dependent AMPK activity.

Alzheimer’s disease (AD) is the most common form of neurodegeneration and cognitive dysfunction in the elderly. Identifying molecular signals that mitigate and reverse neurodegeneration in AD may be exploited therapeutically. Transgenic AD mice (PSAPP) exhibit learning and memory deficits at 9 and 11 months, respectively, with associated decreased expression of caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein necessary for synaptic and neuroplasticity. Neuronal-targeted gene therapy using synapsin-Cav-1 cDNA (SynCav1) was delivered to the hippocampus of PSAPP mice at 3 months using adeno-associated virus serotype 9 (AAV9). Bilateral SynCav1 gene therapy was able to preserve MLRs profile, learning and memory, hippocampal dendritic arbor, synaptic ultrastructure, and axonal myelin content in 9- and 11-month PSAPP mice, independent of reducing toxic amyloid deposits and astrogliosis. Our data indicate that SynCav1 gene therapy may be an option for AD and potentially in other forms of neurodegeneration of unknown etiology.

Abstract Background Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. Methods We established mouse models of CCl4-injured LF and administered hPMSCs at different stages of LF once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. In vitro, the effect of hPMSCs and the secretomes of hPMSCs on the inhibition of activated HSCs was assessed. RNA sequencing (RNA-seq) analysis, real-time PCR array, and western blot were performed to explore possible signaling pathways involved in treatment of LF with hPMSCs. Results hPMSC treatment notably alleviates experimental hepatic fibrosis, restores liver function, and inhibits inflammation. Furthermore, the therapeutic effect of hPMSCs against mild-to-moderate LF was significantly greater than against severe LF. In vitro, we observed that the hPMSCs as well as the secretomes of hPMSCs were able to decrease the activation of HSCs. Mechanistic dissection studies showed that hPMSC treatment downregulated the expression of fibrosis-related genes, and this was accompanied by the upregulation of Caveolin-1 (Cav1) (p < 0.001). This suggested that the amelioration of LF occurred partly due to the restoration of Cav1 expression in activated HSCs. Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. Conclusions Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.

Abstract Objectives Obesity and insulin resistance (IR) are interrelated in a range of ways. The IR-obesity relationship is not a cause-and-effect association. Molecular biology research has made tremendous strides in discovering contributors to find this association. Genes that control adipocyte function such as caveolin-1 (CAV1); probably interact in the pathogenesis of human IR in this context. The involvement of CAV1 in glucose/lipid homeostasis is revealed and could modify the signaling of the insulin receptor. We examined the association between CAV1 and insulin signaling in modifying dyslipidemia and fat composition in overweight and obese women with a prevalent variant in the CAV1 gene. Results Minor allele carriers were slightly older and had higher BMI (p = 0.02), FMI (p = 0.006), and VLF (p = 0.01) values; and tended to have lower total cholesterol TC (p = 0.04), low-density lipoprotein cholesterol (LDL-C) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). HOMA-IR levels predicted fat mass index (FMI) 0.47 (0.08, 0.87), visceral fat level (VFL) 0.65 (0.23, 1.07), TC 6.82 (1.76, 11.88) and HDL-C − 1.663 (− 3.11, − 0.214) only between minor allele carriers in adjusted models. (β, CI). Our results cast a new light on the IR mechanism and future studies will elucidate the clinical relevance of CAV1-IR in patients with dyslipidemia and high fat composition.