The efforts of our last year focus on the role of SIRT1 in metabolism and the phosphorylation regulation of SIRT1. As a highly conserved NAD+-dependent protein deacetylase, SIRT1 has been shown as a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although SIRT1 has been implicated in a number of hepatic metabolic processes, the mechanisms by which hepatic SIRT1 modulates bile acid metabolism are still not well understood. In a recent study, we show that deletion of hepatic SIRT1 reduces the expression of farnesoid X receptor (FXR), a nuclear receptor that regulates bile acid homeostasis. We provide evidence that SIRT1 regulates the expression of FXR through hepatocyte nuclear factor 1α(HNF1α). SIRT1 deficiency in hepatocytes leads to decreased binding of HNF1αto the FXR promoter. Furthermore, we show that hepatocyte-specific deletion of SIRT1 leads to derangements in bile acid metabolism, predisposing the mice to development of cholesterol gallstones on a lithogenic diet. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of hepatic bile acid homeostasis through the HNF1α/FXR signaling pathway. A manuscript describing this study is currently under revision. Although the functions of SIRT1 in many organs have been extensively studied in tissue-specific knockout mouse models, the systemic role of SIRT1 is still largely unknown due to the severe developmental defects of the whole-body knockout mice. Recently we investigated the systemic functions of SIRT1 in metabolic homeostasis utilizing a whole body SIRT1 heterozygous mouse model. These mice are phenotypically normal under standard feeding condition. However, when chronically challenged with a 40%-fat diet, they become obese and insulin-resistant, display increased serum cytokine levels, and develop hepatomegaly. Hepatic metabolomic analyses reveal that SIRT1 Het mice have elevated glyconeogenesis and oxidative stress. However, surprisingly, they are depleted of glycerolipid metabolites and free fatty acids but accumulate lysolipids. Moreover, high-fat feeding induces elevation of serum testosterone levels and enlargement of seminal vesicles in SIRT1 heterozygous males. Microarray analysis of liver mRNA indicates that they have altered expression of genes involved in steroid metabolism and glycerolipid metabolism. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of systemic energy and steroid hormone homeostasis. A manuscript describing this project is submitted. We have previously reported that SIRT1 is activated by phosphorylation at a conserved Thr522 residue in response to environmental stress. In a recent study we demonstrate that phosphorylation of Thr522 activates SIRT1 through modulation of its oligomeric status. We provide evidence that nonphosphorylated SIRT1 protein is aggregation-prone in vitro and in cultured cells. Conversely, phosphorylated SIRT1 protein is largely in the monomeric state. Furthermore, we show that resveratrol is able to prevent non-phosphorylation-induced oligomerization of SIRT1, thereby activating its deacetylase activity and promoting cell survival. Our findings reveal a novel mechanism for environmental regulation of SIRT1 activity, which may have important implications in understanding the molecular mechanism of stress response, cell survival, and aging. A manuscript describing this study is currently under revision.
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