The efforts of our last year focus on the role of SIRT1 in hepatic lipid metabolism. The liver is the central metabolic organ that governs several major aspects of lipid metabolism. Hepatic metabolic derangements are key components in the development of a number of hepatic and systemic metabolic diseases. As the leading member of the sirtuin family, SIRT1 has been shown to play a vital role in the regulation of metabolism and stress responses. However, the tissue-specific and systemic roles of SIRT1 are difficult to dissect in vivo, primarily due to the complicated developmental defects in the whole body SIRT1 knockout mice. To investigate the liver-specific function of SIRT1, we generated SIRT1 Liver specific KO mice (SIRT1 LKO). Through unbiased microarray analyses, we found that the Peroxisome-Proliferator Activated Receptor α(PPARα) signaling pathway is significantly altered in the SIRT1 LKO mice. We then demonstrated that in the liver, a major target of SIRT1 is the PGC-1α/PPARαsignaling pathway and fatty acid oxidation. SIRT1 deficiency results in decreased PPARαsignaling and fatty acid oxidation, whereas increased levels of SIRT1 induces PPARαtranscriptional activity. We further showed that when challenged with a high fat diet, SIRT1 LKO mice develop hepatic stestosis, inflammation, and endoplasmic reticulum stress. These findings provide a direct link between SIRT1 and PPARα/PGC-1α- mediated fatty acid oxidation, and defining a new role for SIRT1 as a key regulator of hepatic lipid metabolism. A paper described these findings was published in Cell Metabolism in April of 2009. While much attention has been focused on the identification of cellular targets to explore the molecular mechanisms and functional networks controlled by SIRT1, how SIRT1 activity is regulated is still unclear. Therefore, another focus of our group is to understand the molecular mechanism that controls SIRT1 expression and activity. In one of our recent studies, we demonstrated that two anti-apoptotic members of the dual-specificity tyrosine-phosphorylated and regulated kinase (DYRK) family, DYRK1A and DYRK3, interact with SIRT1 in vitro and in vivo. We discovered that both DYRK1A and DYRK3 directly phosphorylate SIRT1 at the Threonine 522 residue that is located within a predicted α-helix linker region adjacent to the C-terminus of its catalytic core domain. DYRK-mediated phosphorylation of SIRT1 increases its activity, resulting in deacetylation and inhibition of p53 upon DNA damage. Whereas a SIRT1 mutant that is incapable of being phosphorylated by DYRK fails to deacetylate p53, thus promoting cell apoptosis. Furthermore, knockdown of endogenous DYRK1A and DYRK3 leads to hypo-phosphorylation of SIRT1, sensitizing cells to DNA damage-induced cell death. Our findings further indicated that anti-apoptotic DYRK members stimulate cell survival through modification of SIRT1. This study adds a new layer in the regulatory network that regulates SIRT1 activity and has important implications in understanding the molecular mechanism of tumorigenesis and aging.
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