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...

ATP-binding cassette transporter A1 (ABCA1) is a plasma membrane protein that functions to eliminate excess free cholesterol (FC) from tissues by effl uxing cellular FC and phospholipid (PL) to lipid-free apolipoprotein AI, forming nascent HDL particles ( 1, 2 ). Therefore, ABCA1 plays a critical role in the movement of cholesterol from peripheral tissues to the liver in a process known as reverse cholesterol transport. Mutations that inactivate the human ABCA1 gene result in Tangier disease, which is characterized by extremely low plasma HDL cholesterol concentrations, mildly elevated plasma triglyceride levels, and accumulation of cholesterol in macrophages ( 3-5 ). ABCA1 protein is expressed to a variable extent in most cells in the body, and its expression is regulated by transcriptional activation and protein degradation ( 6, 7 ), making it diffi cult to determine HL-49373, HL-094525, and AT-27820 (J.S.P.) Ϫ / Ϫ , total Abca1 knockout; ABCG1, ATP-binding cassette transporter G1; BMDM, bone marrow-derived macrophage; CT-B, cholera toxin B; FC, free cholesterol; fPEG-chol, fl uorescein ester of polyethylene glycol-derivatized Macrophage ABCA1 reduces MyD88-dependent Toll-like This work was supported by National Institutes of Health Grants

Lipid rafts and caveolae play a pivotal role in organization of signaling by Toll-like Receptor (TLR)4 and several other immune receptors. Beyond the simple cataloguing of signaling events compartmentalized by these membrane microdomains, recent studies have revealed the surprisingly central importance of dynamic remodeling of membrane lipid domains to immune signaling. Simple interventions upon membrane lipid, such as changes in cholesterol loading or crosslinking of raft lipids, are sufficient to induce micron-scale reordering of membranes and their protein cargo with consequent signal transduction. In this review, using TLR signaling in the macrophage as a central focus, we discuss emerging evidence that environmental and genetic perturbations of membrane lipid regulate protein signaling, illustrate how homeostatic flow of cholesterol and other lipids through rafts regulates the innate immune response, and highlight recent attempts to harness these insights towards therapeutic development.