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Deacetylation of XBP1s by sirtuin 6 confers resistance to ER stress-induced hepatic steatosis

Experimental & Molecular Medicine 2019년 51권 9호 p.107 ~ 107
 ( Bang In-Hyuk ) - Chonbuk National University Medical School Department of Biochemistry

 ( Kwon Oh-Kwang ) - Kyungpook National University College of Pharmacy
 ( Hao Lihua ) - Chonbuk National University Medical School Department of Biochemistry
 ( Park Da-Mi ) - Chonbuk National University Medical School Department of Biochemistry
 ( Chung Myung-Ja ) - Chonbuk National University Medical School Department of Biochemistry
 ( Oh Byung-Chul ) - Gachon University College of Medicine Department of Physiology
 ( Lee Sang-Kyu ) - Kyungpook National University College of Pharmacy
 ( Bae Eun-Ju ) - Chonbuk National University College of Pharmacy
 ( Park Byung-Hyun ) - Chonbuk National University Medical School Department of Biochemistry

Abstract


The active spliced form of X-box-binding protein 1 (XBP1s) is a key modulator of ER stress, but the functional role of its post-translational modification remains unclear. Here, we demonstrate that XBP1s is a deacetylation target of Sirt6 and that its deacetylation protects against ER stress-induced hepatic steatosis. Specifically, the abundance of acetylated XBP1s and concordant hepatic steatosis were increased in hepatocyte-specific Sirt6 knockout and obese mice but were decreased by genetic overexpression and pharmacological activation of Sirt6. Mechanistically, we identified that Sirt6 deacetylated a transactivation domain of XBP1s at Lys257 and Lys297 and promoted XBP1s protein degradation through the ubiquitin-proteasome system. Overexpression of XBP1s, but not its deacetylation mutant 2KR (K257/297R), in mice increased lipid accumulation in the liver. Importantly, in liver tissues obtained from patients with nonalcoholic fatty liver disease (NAFLD), the extent of XBP1s acetylation correlated positively with the NAFLD activity score but negatively with the Sirt6 level. Collectively, we present direct evidence supporting the importance of XBP1 acetylation in ER stress-induced hepatic steatosis.

키워드

Non-alcoholic fatty liver disease; Translational research
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