Loss of Small Valosin-containing Protein-Interacting Protein (SVIP) in Rat Hepatoma cells Causes Increased Intracellular Retention of Very Low-Density Lipoproteins (VLDL)
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PROVIDER: PRJNA1224227 | ENA |
REPOSITORIES: ENA
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Project description:In the current study we have generated a CRISPR-Cas9 mediated SVIP knockout rat hepatoma cell line with the goal to further understand the functional role of SVIP in the complex process of VLDL transport and secretion. We observed that complete absence of SVIP protein results in enhanced retention of VLDL in the hepatoma cells. This was marked by both an increased expression of apoB100 protein and neutral lipid staining detected inside SVIP knockout (SVIP KO) cells. Furthermore, RNA sequencing studies of the SVIP KO hepatoma cells revealed a significant downregulation of genes within the peroxisome proliferator- activated receptor alpha (PPAR alpha) and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, thereby affecting hepatic fatty acid (FA) metabolism. Most importantly, we observed that cells lacking SVIP demonstrated a substantial down regulation of another very important gene associated with FA metabolism, namely the liver fatty acid-binding protein (L-FABP). Additionally, the RNAseq data also reveals that the loss of SVIP thrusts the hepatoma cells into an acute phase response (APR) like state, with an increase in the expression of protein synthesis genes.
2025-08-20 | GSE289707 | GEO
Project description:Triglyceride-rich lipoproteins and their remnants contribute to atherosclerosis, possibly by carrying remnant cholesterol and/or by exerting a pro-inflammatory effect on macrophages. Nevertheless, little is known about how macrophages process triglyceride-rich lipoproteins. We show that uptake by macrophages of VLDL-sized emulsion particles is dependent on the enzyme lipoprotein lipase via its C-terminal domain. Subsequent internalization of VLDL-triglycerides by macrophages is carried out by caveolae-mediated endocytosis, followed by hydrolysis by lysosomal acid lipase. STARD3 is required for the transfer of lysosomal fatty acids to the ER for lipid storage, while NPC1 likely is involved in promoting the extracellular efflux of fatty acids. Our data provide novel insights into how macrophages process VLDL-derived triglycerides and suggest that macrophages have the remarkable capacity to excrete internalized triglycerides as fatty acids.
2022-05-21 | GSE203250 | GEO
Project description:Cytochrome P450, family 7, subfamily b, polypeptide 1(CYP7B1) is a widely expressed hydroxylase enzyme that may be involved in inactivation of sterols. Using transposon in zygotes, we have generated rats lacking Cyp7b1 expression. Homozygous mutant animals show absence of Cyp7b1 mRNA expression in liver, small intestine, adipose tissue and muscle. Elevated levels of 25-hidroxycholesterol were found in liver of mutant rats. A fat gavage test showed that postprandial hypertriglyceridemia was decreased in homozygotes lacking Cyp7b1 without changes in cholesterol, APOA1 and APOA4 contents of postprandial lipoproteins. In this experimental setting, gene expression analyses of those coding for proteins involved in HDL structure and metabolism revealed that only hepatic Abca1 mRNA expression was significantly decreased. A four-hour fasting had no impact on plasma lipids. However, after prolonged fasting, plasma triglyceride levels in the homozygous mutants were increased about 164 % of wild types. In agreement with this, an increased hepatic secretion of VLDL in fasting rats treated with tyloxapol and absence of low-density receptor protein on the surface of hepatocytes were observed. The decrease in LDLr was not due to decreased mRNA expression but to increased expression of its protease Psck9. These data indicate that CYP7B1 and its metabolite 25-hydroxycholesterol modulates the metabolism of VLDL in liver by decreasing its capture by LDL receptor. In agreement with this, an increased hepatic secretion of VLDL in fasting rats treated with tyloxapol and absence of low-density receptor protein on the surface of hepatocytes were observed. The decrease in LDLr was not due to decreased mRNA expression but to increased expression of its protease Psck9. These data indicate that CYP7B1 and its metabolite 25-hydroxycholesterol modulates the metabolism of VLDL in liver by decreasing its capture by LDL receptor. These observations were partially recovered by exogenous plasmid hydrodinamic injection
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Project description:The PPAR? activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. After 4 hours fasting, livers were isolated and individual gene arrays were performed.
2010-05-27 | E-GEOD-21211 | biostudies-arrayexpress
Project description:Very low-density lipoprotein (VLDL) receptor (VLDLR), a member of the low-density lipoprotein receptor family, is responsible for VLDL uptake in peripheral tissues. We reported that significant increase in hepatic VLDLR levels following protein restriction in male mice does not contribute to hepatic fat accumulation, indicating that VLDLR may have hitherto unknown functions. Here, we used RNA-sequencing analysis of liver samples to analysis the effects of protein restriction on hepatic VLDLR in male and female mice.
2024-02-27 | GSE259313 | GEO
Project description:Although hypertriglyceridemia and postprandial lipemia associate with greater atherosclerosis, partially metabolized triglyceride-rich lipoproteins termed remnants rather than nascent lipoproteins have been implicated as the culprits. Whether chylomicrons are inherently atherogenic remains unclear. To test whether increased levels of nascent triglyceride-rich lipoproteins (TRLs) in the absence of markedly reduced LDL-C levels contribute to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl-/-) and LDLR knockdown (Ldlrkd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl-/-/Ldlrkd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that non-remnant TRLs are not benign.
2025-09-15 | GSE307653 | GEO
Project description:The PPARα activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.
2010-05-27 | GSE21211 | GEO
Project description:Endocannabinoids belong to a diverse family of endogenous lipid bioregulators acting as physiological ligands of cannabinoid receptor type 1 and cannabinoid receptor type 2 in the central and peripheral nervous system. They are also present in nmol/l concentrations in human blood plasma; however, their association with possible molecular carriers remains poorly characterized. Here we report on the quantification of 46 endogenous molecular species from five major classes of endocannabinoids and endocannabinoid-related compounds in three lipoprotein fractions of human blood plasma: (VLDL), LDL, HDL, and in the plasma lipoproteinfree fraction. Although sizable quantities of endocannabinoid related molecules are associated with lipoproteins, we identified the lipoprotein-free fraction as a major carrier of endocannabinoids in blood circulation with the exception of 2-acylglycerols, which are markedly abundant in VLDL.
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Project description:Genetic polymorphisms that impair VLDL secretion are linked to hepatic steatosis, fibrosis and hepatocellular cancer (HCC). Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO mice with germline Fabp1 deletion (Fabp1/Mttp DKO) mice. Here we examine the impact of impaired VLDL secretion in Mttp-LKO mice on HCC incidence and progression in comparison to Fabp1/Mttp DKO mice. DEN treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared to flox controls, while diethylnitrosamine (DEN)- treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNAseq analysis performed on liver tissue at 6 months revealed mRNA changes suggesting altered monocarboxylic acid utilization and increased aerobic glycolysis, while hepatocytes from Fabp1/Mttp DKO mice exhibited increased capacity to utilize glucose and glutamine. Taken together, these findings demonstrate that hepatic tumorigenesis is increased in mice with impaired VLDL secretion and further accelerated via pathways including altered fatty acid compartmentalization and shifts in hepatic energy utilization.
2024-02-12 | GSE253701 | GEO