Abstract
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.
Highlights
Cholesterol homeostasis is crucial for cellular function and organismal health
Sirt6 regulates hepatic cholesterol homeostasis in vivo Previously, it has been shown that Sirt6 plays a critical role in hepatic triglyceride metabolism [45]
Because sterol-regulatory element binding protein (SREBP)-2 is the key regulator of cholesterol biosynthesis, we analyzed both the precursor and mature nuclear forms of SREBP-2 in the control and sirtuin 6 liver-specific knockout (LKOT6) livers
Summary
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. It has been shown that deacetylation of SREBP-1/2 by Sirt destabilizes these proteins [20, 21] Another Sirt family member, Sirt, has been increasingly appreciated for its broad role in biology, including genome maintenance and DNA repair [22,23,24,25,26,27,28,29], cell survival and apoptosis [30,31,32], inflammation [33,34,35,36,37,38], cardiac function [39,40,41], oxidative stress [42], longevity [43], and metabolism and energy homeostasis [44,45,46,47,48,49,50,51]. Sirt has been shown to regulate glycolysis and fatty acid synthesis and metabolism through deacetylation of H3K9 and H3K56, and Sirt liver-specific knockout (LKOT6) mice develop fatty liver disease [45]
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