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Disruption of the Cyp7b1 Gene in Rats Increases Secretion of Very Low Density Lipoproteins by Decreasing Low Density Lipoprotein Receptor on Plasma Membrane

ABSTRACT: 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

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE267177 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

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Disruption of the Cyp7b1 Gene in Rats Increases Secretion of Very Low Density Lipoproteins by Decreasing Low Density Lipoprotein Receptor on Plasma Membrane

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