Hepatic gene expression data from Gpr146 WT and KO male mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139082 | GEO | 2019/11/27
REPOSITORIES: GEO
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Project description:If the function of the nuclear receptor PPARa is well-known during a prolongated fasting, its hepatic biological function during feeding and refeeding conditions still needs to be investigated. Moreover, in vivo data collected so far on PPARa function during fasting were obtained using the total Ppara KO transgenic mouse model. To identify genes whose expression is under the strict dependence of hepatic PPARa activity, we generated a new mouse strain of PPARa-specific deletion in hepatocyte (albumin-Cre+/- Pparaflox/flox or LKO) and we compared them to total Ppara KO (KO), wild-type (WT) and liver WT (albumin-Cre-/- Pparaflox/flox or LWT) mice under three nutritional challenges. We used microarrays to detail the global programme of gene expression in liver of Ppara LKO, LWT, Ppara KO and WT male mice fed ad libitum, fasted for 24 hours and refed. There are 52 liver samples, each from an individual mouse. The samples are from Ppara liver KO (LKO), Ppara KO (KO), wild-type (WT) and liver WT (LWT) male mice of 8 week-old from the same genetic background (C57Bl/6J) fed ad libitum, fasted for 24 hours, fasted for 24 hours and then refed 24 hours more with glucose added in water (200g/l). In fed condition (Fed), n= 3 mice for LKO, LWT genotypes, n= 5 for KO and n= 4 fot WT; in fasting condition (Fas), n=5 for LKO, LWT and WT genotypes and n= 3 for KO; in refeeding condition (Ref), n= 5 for LKO, KO and WT genotypes and n= 4 for LWT. All mice were sacrified at ZT14.
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Project description:In cell models, changes in the “accessible” pool of plasma membrane (PM) cholesterol are linked with the regulation of ER sterol synthesis and metabolism by the Aster family of nonvesicular transporters. However, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in liver: fasting and reverse cholesterol transport (RCT). During fasting, adipose tissue–derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester (CE) formation, cholesterol movement into bile, and VLDL production. During RCT, HDL delivers excess cholesterol to the hepatocyte PM through SR-BI. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels, and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.
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Project description:Background Small intestine and liver greatly contribute to whole body lipid, cholesterol and phospholipid metabolism but to which extent cholesterol and phospholipid handling in these tissues is affected by high fat Western-style obesogenic diets remains to be defined. We therefore quantified cholesterol and phospholipid concentrations in intestine and liver and determined fecal neutral sterol and bile acid excretion in C57Bl/6N mice fed for 12 weeks either a cholesterol-free high carbohydrate control diet or a high fat diet containing 0.03 % (w/w) cholesterol. To identify underlying mechanisms of dietary adaptation in intestine and liver, changes in gene expression were assessed by microarray and qPCR profiling, respectively. Results Animals on high fat diet showed increased plasma cholesterol levels, associated with the higher dietary cholesterol supply, yet, significantly reduced cholesterol levels were found in intestine and liver. Transcript profiling revealed evidence that expression of numerous genes involved in cholesterol synthesis and uptake via LDL, but also in phospholipid metabolism, underwent compensatory regulations in both tissues. Alterations in glycerophospholipid metabolism were confirmed at the metabolite level by phospolipid profiling via mass spectrometry. Conclusions Our findings suggest that intestine and liver react to a high dietary fat intake by an activation of de novo cholesterol synthesis and other cholesterol-saving mechanisms, as well as with major changes in phospholipid metabolism, to accommodate to the fat load. The proximal part of the intestine of mice fed either a control or a high fat diet were analyzed. 5 replicates each.
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Project description:The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. Owing to their central role in controlling hepatic lipid and lipoprotein metabolism their activity is tightly coordinated, and accordingly dysregulation of the SREBP pathway is associated with development of dyslipidemia and non-alcoholic fatty liver disease. Using a suite of genome-wide genetic screens we have recently identified SPRING (C12ORF49) as a novel post-transcriptional regulator of SREBP activation in vitro. Our previous work demonstrated that constitutive ablation of Spring in mice is embryonically lethal. Here we show that inducible global deletion of Spring is also untolerated, and therefore to interrogate the physiological role of SPRING in controlling hepatic lipid metabolism we developed liver-specific Spring knockout mice (LKO). Liver transcriptomics and proteomics analysis revealed severely attenuated SREBP signaling in livers and in hepatocytes of LKO mice, which was associated with marked effects on both plasma and hepatic lipid levels. In plasma, total cholesterol levels were dramatically reduced in both male and female LKO mice, apparent in both the LDL and HDL fractions, while triglyceride levels remained largely unaffected. In liver, loss of Spring diminished cholesterol and triglyceride biosynthesis resulting in decreased hepatic cholesterol and triglyceride content. This coincided with reduced secretion of VLDL into the circulation. Consistent with diminished hepatic de novo lipogenesis, LKO mice were protected from developing hepatosteatosis when challenged with a fructose-rich diet. Supporting the significance of our findings in mice, we identified common and rare SPRING genetic variants that are strongly associated with circulating HDL-c and ApoA1 levels in humans. Collectively, our study positions SPRING as a core component of hepatic SREBP signaling, and consequently of systemic lipid metabolism in mice and humans.
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