Abstract
Hepatocyte is a hub for cholesterol metabolism. Augmented synthesis of cholesterol in the liver is associated with hypercholesterolemia and contributes to the pathogenesis of a host of cardiovascular and metabolic diseases. Sterol response element binding protein 2 (SREBP2) regulates hepatic cholesterol metabolism by activating the transcription of rate-limiting enzymes in the cholesterol biosynthesis pathway. The underlying epigenetic mechanism is not well understood. We report here that mice with hepatocyte-specific knockout (CKO) of Brg1, a chromatin remodeling protein, exhibit reduced levels of hepatic cholesterol compared to the wild type (WT) littermates when placed on a high-fact diet (HFD) or a methionine-and-choline-deficient diet (MCD). Down-regulation of cholesterol levels as a result of BRG1 deficiency was accompanied by attenuation of cholesterogenic gene transcription. Likewise, BRG1 knockdown in hepatocytes markedly suppressed the induction of cholesterogenic genes by lipid depletion formulas. Brg1 interacted with SREBP2 and was recruited by SREBP2 to the cholesterogenic gene promoters. Reciprocally, Brg1 deficiency dampened the occupancies of SREBP2 on target promoters likely through modulating H3K9 methylation on the cholesterogenic gene promoters. Mechanistically, Brg1 recruited the H3K9 methyltransferase KDM3A to co-regulate pro-cholesterogenic transcription. KDM3A silencing dampened the cholesterogenic response in hepatocytes equivalent to Brg1 deficiency. In conclusion, our data demonstrate a novel epigenetic pathway that contributes to SREBP2-dependent cholesterol synthesis in hepatocytes.
Highlights
Cholesterol is an important bioactive lipid that plays a wide range of physiological and pathophysiological roles
Expression levels of several enzymes involved in the cholesterol biosynthesis pathway, including 3hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (Hmgcs1), and squalene monooxygenase (Sqle), were all down-regulated in the livers of conditional BRG1 knockout (CKO) mice than wild type (WT) mice (Figures 1B,C)
Our new findings as summarized in this report demonstrate that brahma related gene 1 (BRG1) may contribute to cholesterol biosynthesis by functioning as a co-factor for Sterol response element binding protein 2 (SREBP2) to activate the transcription of cholesterogenic genes
Summary
Cholesterol is an important bioactive lipid that plays a wide range of physiological and pathophysiological roles. Recent studies have suggested that cholesterol may contribute to innate immunity and host defense (Reboldi and Dang, 2018). Excessive cholesterol synthesis is associated with hypercholesterolemia and a host of cardiovascular and metabolic diseases. Hepatocytes are the primary source of cholesterol production. Over-production of cholesterol can often be attributed to up-regulation of the enzymes involved in its biosynthetic pathway in the liver. As a matter of fact, statins, widely used to treat dyslipidemia and coronary heart disease (CHD), target 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme for cholesterol biosynthesis (Levy et al, 1993)
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