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KMID : 0811720150190050451
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Korean Journal of Physiology & Pharmacology
2015 Volume.19 No. 5 p.451 ~ p.460
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Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice
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Kim Kyung-Eun
Kim Hwa-Jin
Heo Rok-Won
Shin Hyun-Joo
Yi Chin-Ok
Lee Dong-Hoon
Kim Hyun-Joon
Kang Sang-Soo
Cho Gyeong-Jae
Choi Wan-Sung
Roh Gu-Seob
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Abstract
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Sirtuin 1 (SIRT1) is a mammalian NAD＋-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflam-mation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation con-tributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic path-way through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.
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KEYWORD
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Hepatic steatosis, High-fat diet, Nuclear factor kappa B, Sirtuin 1
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