Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6

Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, Sirt6 or FoxO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice. In summary, our data suggest an important role of hepatic Sirt6 and FoxO3 in the regulation of cholesterol homeostasis. Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, Sirt6 or FoxO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice. In summary, our data suggest an important role of hepatic Sirt6 and FoxO3 in the regulation of cholesterol homeostasis. 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In this we have identified a by which Sirt6 to the promoter of the Srebp2 gene and the gene expression and Sirt6 been to numerous genes histone including fatty acid and Xiao C. T. X. A. G. O. et of in mice in fatty liver formation to and Metab. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). Hepatic deficiency of Sirt6 leads to fatty liver in mice Xiao C. T. X. A. G. O. et of in mice in fatty liver formation to and Metab. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). In to of Srebp2 by and of SREBP-2 protein by a been SREBP the protein and B. Xiao Z. Z. J. M. deacetylates and in regulation of hepatic lipid Biol. Chem. 2010; 285: Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. K. D.M. T. M. F. et regulates in 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, M. E. J. of the SREBP of transcription Biol. 23: PubMed Scopus Google Scholar). regulate the rate-limiting in the of biosynthesis as deficiency causes a in in a in R. D. Y. DePinho R.A. Hepatic regulate lipid metabolism of expression of the Biol. Chem. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). can cholesterol homeostasis of gene expression and cholesterol X. Zhang S. G. M. L. deacetylates and regulates the nuclear Full Text Full Text PDF PubMed Scopus Google Scholar). been in cholesterol homeostasis in R.A. Han S. Accili D. Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia.J. Biol. Chem. 2010; 285: 26861-26868Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 14Zhang K. Li L. Qi Y. Zhu X. Gan B. DePinho R.A. Averitt T. Guo S. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice.Endocrinology. 2012; 153: 631-646Crossref PubMed Scopus (112) Google Scholar, 15Zhang W. Patil S. Chauhan B. Guo S. Powell D.R. Le J. Klotsas A. Matika R. Xiao X. Franks R. et al.FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.J. Biol. Chem. 2006; 281: 10105-10117Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 17Zhu J. Mounzih K. Chehab E.F. Mitro N. Saez E. Chehab F.F. Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake.J. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, A. FoxO1 insulin to 2008; 7: PubMed Scopus Google Scholar, M. A. L. R.A. Accili D. regulation of hepatic glucose in mice the forkhead transcription factor Foxo1 in Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). mice FoxO1 in the liver have and mice are not W. Patil S. Chauhan B. Guo S. Powell D.R. Le J. Klotsas A. Matika R. Xiao X. Franks R. et al.FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.J. Biol. Chem. 2006; 281: 10105-10117Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar). FoxO1 in the liver of mice cholesterol, mice not a in cholesterol K. Li L. Qi Y. Zhu X. Gan B. DePinho R.A. Averitt T. Guo S. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice.Endocrinology. 2012; 153: 631-646Crossref PubMed Scopus (112) Google Scholar, A. FoxO1 insulin to 2008; 7: PubMed Scopus Google Scholar, M. A. L. R.A. Accili D. regulation of hepatic glucose in mice the forkhead transcription factor Foxo1 in Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). the by hepatic FoxO1 deficiency leads to elevated cholesterol and a in Srebp2 in the liver R.A. Han S. Accili D. Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia.J. Biol. Chem. 2010; 285: 26861-26868Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). are in our FoxO1 is not a in hepatic cholesterol biosynthesis physiological our data suggest a role of FoxO3 in this the in granulosa FoxO3 can Srebp2 gene expression in this Z. Rudd M.D. Hernandez-Gonzalez I. Gonzalez-Robayna I. Fan H.Y. Zeleznik A.J. Richards J.S. FSH and FOXO1 regulate genes in the sterol/steroid and lipid biosynthetic pathways in granulosa cells.Mol. Endocrinol. 2009; 23: 649-661Crossref PubMed Scopus (127) Google Scholar). a role of FoxO3 in cholesterol homeostasis, in cholesterol is in the to the K. Li L. Qi Y. Zhu X. Gan B. DePinho R.A. Averitt T. Guo S. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice.Endocrinology. 2012; 153: 631-646Crossref PubMed Scopus (112) Google Scholar). In our hepatic and cholesterol are elevated in hepatic mice. With regard to overexpression in expression of cholesterol biosynthetic genes and and cellular cholesterol J. Mounzih K. Chehab E.F. Mitro N. Saez E. Chehab F.F. Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake.J. 2010; Full Text Full Text PDF PubMed Scopus Google FoxO4 mice not in cholesterol K. Li L. Qi Y. Zhu X. Gan B. DePinho R.A. Averitt T. Guo S. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice.Endocrinology. 2012; 153: 631-646Crossref PubMed Scopus (112) Google Scholar). suggest in cholesterol regulation, FoxO3 plays a role in this we have a between and Sirt6 in cholesterol homeostasis. is Sirt6 have effects on histone H3 however, our data suggest transcription factors as have the to this to a of at for the of cholesterol regulation. The of Sirt6 and have in the regulation of have been linked to this Y. S. G. G. L. Z. H.Y. 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In summary, of or of FoxO3 can Sirt6 to the Srebp2 gene thereby a to expression of Srebp2 and In to insulin and factors can and of the of a and are and a for FoxO3 and Sirt6 can to regulate cholesterol homeostasis and organismal health. The for FoxO3 chromatin forkhead box O protein histone H3 at 9 histone H3 at 3-hydroxy-3-methylglutaryl-CoA reductase insulin FoxO1 FoxO3 sirtuin mature nuclear form of sterol-regulatory element binding protein sirtuin sterol-regulatory element binding protein