Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network
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ABSTRACT:
PROVIDER: PRJNA450545 | ENA |
REPOSITORIES: ENA
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Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked to altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity and hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
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2021-09-10 | GSE183790 | GEO
Project description:An improved mechanistic understanding of the thyroid hormone (TH) action on bile acid (BA) synthetic pathway, the major route for cholesterol elimination, will facilitate the identification of novel therapeutic targets for hypercholesterolemia. Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces the serum cholesterol levels, which is accompanied with an upregulation of key enzymes involved in the intrahepatic conversion of cholesterol to BAs. Importantly, transgenic mice with liver-specific and moderate overexpression of miR-378 also display a decrease in serum cholesterol levels accompanied with an enhanced BA synthesis and are resistant to diet-induced hypercholesterolemia. In contrast, mice lacking miR-378 exhibit an elevation of serum cholesterol levels accompanied with an impaired BA synthesis. Mechanistic studies reveal that hepatic miR-378 regulates BA synthesis and cholesterol homeostasis through its direct target gene MAFG, which is a transcriptional repressor of BA synthetic genes. We also show that miR-378 serves as an essential component in either incoherent or coherent feed-forward loop to confer robust and precise controls on BA synthesis in response to TH signalling. Together, we identify a previously undescribed miR-378-mediated mechanism underlying the cholesterol-lowering effect of TH. Our findings not only add a new dimension to our understanding the regulation of BA synthesis by TH, but also provide new therapeutic regimens to manage serum cholesterol levels
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Project description:Purpose: PCSK9, which regulates hepatic lipid homeostasis by modulating LDL levels, is expressed in small quantities in the heart, but its role is unknown. Here, we sought to determine its cardiac function and identify the mechanisms. Mice with heart-specific deletion of Pcsk9 had reduced contractile capacity, heart failure with preserved ejection fraction, and left ventricular dilatation at 28 weeks of age and died prematurely. Results: Transcriptomic analyses revealed alterations of signaling pathways linked to cardiomyopathy and energy metabolism. Mitochondrial membrane lipid composition and cristae morphology were also altered, impairing the assembly and activity of mitochondrial respiratory complexes. Mitochondrial oxidation was reduced and compensatory glycolytic energy production was insufficient to support demand. Conclusions: Thus, PCSK9 is a key factor in cardiac metabolic function and PCSK9 deficiency is linked to cardiomyopathy, impaired heart function, and compromised energy production.
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