SUMMARY Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating PPARα, a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of SIRT1 induces the expression of PPARα targets. SIRT1 interacts with PPARα and is required to activate PPARα co-activator PGC-1α. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis, and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.

The NAD(+)-dependent deacetylase Sir2 regulates life span in lower eukaryotes. The mammalian ortholog SIRT1 regulates physiological processes including apoptosis, fat metabolism, glucose homeostasis, and neurodegeneration. Here we show that SIRT1 is a positive regulator of liver X receptor (LXR) proteins, nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRalpha and K433 in LXRbeta) adjacent to the ligand-regulated activation domain AF2. SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRalpha by this sirtuin. Loss of SIRT1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis. Our findings suggest that deacetylation of LXRs by SIRT1 may be a mechanism that affects atherosclerosis and other aging-associated diseases.

Macrophage activation and infiltration into resident tissues is known to mediate local inflammation and is a hallmark feature of metabolic syndrome. Members of the sirtuin family of proteins regulate numerous physiological processes, including those involved in nutrient regulation and the promotion of longevity. However, the important role that SIRT1, the leading sirtuin family member, plays in immune response remains unclear. In this study, we demonstrate that SIRT1 modulates the acetylation status of the RelA/p65 subunit of NF-B and thus plays a pivotal role in regulating the inflammatory, immune, and apoptotic responses in mammals. Using a myeloid cell-specific SIRT1 knockout (Mac-SIRT1 KO) mouse model, we show that ablation of SIRT1 in macrophages renders NF-B hyperacetylated, resulting in increased transcriptional activation of proinflammatory target genes. Consistent with increased proinflammatory gene expression, Mac-SIRT1 KO mice challenged with a high-fat diet display high levels of activated macrophages in liver and adipose tissue, predisposing the animals to development of systemic insulin resistance and metabolic derangement. In summary, we report that SIRT1, in macrophages, functions to inhibit NF-B-mediated transcription, implying that myeloid cell-specific modulation of this sirtuin may be beneficial in the treatment of inflammation and its associated diseases.Chronic inflammation is increasingly recognized as a causal factor leading to the development of obesity, insulin resistance, and type 2 diabetes (15, 31). This low-grade inflammatory state is in part mediated by macrophages, key sentinels of the innate immune system. Macrophages quiescently monitor the tissue milieu for signs of infection or damage (13,25). Upon stimulation, macrophages infiltrate resident tissue, perpetuating local inflammation and contributing to the development of insulin resistance and metabolic derangements (17,37,43). The nuclear factor kappa B (NF-B) transcription factor signaling pathway is a key mediator of immune response in macrophages (5, 7). NF-B is composed of a heterodimer of p50 and RelA/ p65 subunits. In unstimulated cells, NF-B resides in the cytoplasm bound to its inhibitory proteins, which are members of the inhibitor of B (IB) family. Stimulation of cells by environmental factors, including dietary fatty acids, liberates NF-B, allowing it to translocate to the nucleus, where it mediates gene transcription (12). Under environmental stresses, such as those surrounding obesity-like conditions, this chain of events is believed to ultimately lead to insulin resistance, setting in motion the vicious cycle of the metabolic syndrome.Sirtuins are highly conserved NAD ϩ -dependent deacetylases that target histones, transcription factors, coregulators, and other key regulators to adapt gene expression and metabolism to the cellular energy state (16,22,32). SIRT1, the leading family member, has been reported to promote longevity in species ranging from yeast to flies (1)(2)(3)6). It is believed that these life-exte...

Sirtuin 1 (SIRT1) is the most conserved mammalian NAD(+)-dependent protein deacetylase that has emerged as a key metabolic sensor in various metabolic tissues. In response to different environmental stimuli, SIRT1 directly links the cellular metabolic status to the chromatin structure and the regulation of gene expression, thereby modulating a variety of cellular processes such as energy metabolism and stress response. Recent studies have shown that SIRT1 controls both glucose and lipid metabolism in the liver, promotes fat mobilization and stimulates brown remodeling of the white fat in white adipose tissue, controls insulin secretion in the pancreas, senses nutrient availability in the hypothalamus, influences obesity-induced inflammation in macrophages, and modulates the activity of circadian clock in metabolic tissues. This review focuses on the role of SIRT1 in regulating energy metabolism at different metabolic tissues.