S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis

doi:10.1016/j.jcmgh.2020.10.006

	S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis
	Zhang, Linqiang 5,6,7,8; Zhang, Zhiguo 8; Li, Chengbin 5; Zhu, Tingting 8; Gao, Jing 9,10; Zhou, Hu 9,10; Zheng, Yingzhuan 11; Chang, Qing 5,8; Wang, Mingshan 3; Wu, Jieyu 8
刊名	CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
	2021
卷号	11 期号:3 页码:697-724
关键词	NAFLD S100A11 FOXO1 Autophagy Lipid Metabolism
ISSN号	2352-345X
DOI	10.1016/j.jcmgh.2020.10.006
通讯作者	Wu, Yingjie(yyjjwu@yahoo.com) ; Miao, Huilai(627225370@qq.com) ; Zou, Xiaoju(xiaojuzou@163.com) ; Liang, Bin(liangb73@ynu.edu.cn)
英文摘要	BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. METHODS: We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. RESULTS: The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid-treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1-6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. CONCLUSIONS: A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.
资助项目	Ministry of Science and Technology of the People's Republic of China[2018YFA0800700] ; National Natural Science Foundation of China[81700520] ; National Natural Science Foundation of China[U1702288] ; National Natural Science Foundation of China[U1702287] ; National Natural Science Foundation of China[31671230] ; National Natural Science Foundation of China[91857113] ; National Natural Science Foundation of China[31860323] ; Yunnan Applied Basic Research Projects[2017FA007] ; Yunnan Applied Basic Research Projects[2018FB117] ; Yunnan Applied Basic Research Projects[2019FY003021] ; Yunnan Oversea High-level Talents Program[2015HA039] ; Yunnan Oversea High-level Talents Program[2015HA040] ; Open Program of the Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences[AMHD-2018-6] ; Yunnan Province[AMHD-2018-6]
WOS研究方向	Gastroenterology & Hepatology
语种	英语
出版者	ELSEVIER INC
WOS记录号	WOS:000621254400003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295514]
专题	中国科学院上海药物研究所
通讯作者	Wu, Yingjie; Miao, Huilai; Zou, Xiaoju; Liang, Bin
作者单位	1.Dalian Med Univ, Inst Genome Engn Anim Models Human Dis, Dalian, Liaoning, Peoples R China 2.Yunnan Univ Chinese Med, Sch Tradit Chinese Med, Kunming, Yunnan, Peoples R China 3.Univ Calif Santa Cruz, Howard Hughes Med Inst, Dept Ecol & Evolutionary Biol, Santa Cruz, CA 95064 USA 4.Shandong First Med Univ, Shandong Acad Med Sci, Sci & Technol Innovat Ctr, Shandong Lab Anim Ctr, Jinan, Shandong, Peoples R China 5.Yunnan Univ, Ctr Life Sci, Sch Life Sci, Kunming, Yunnan, Peoples R China 6.Guangdong Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Zhanjiang, Guangdong, Peoples R China 7.Guangdong Med Univ, Affiliated Hosp, Dept Hepatobiliary Surg, Zhanjiang, Guangdong, Peoples R China 8.Chinese Acad Sci, Chinese Acad Sci & Yunnan Prov, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech, Kunming, Yunnan, Peoples R China 9.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai, Peoples R China 10.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Linqiang,Zhang, Zhiguo,Li, Chengbin,et al. S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis[J]. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY,2021,11(3):697-724.
APA	Zhang, Linqiang.,Zhang, Zhiguo.,Li, Chengbin.,Zhu, Tingting.,Gao, Jing.,...&Liang, Bin.(2021).S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis.CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY,11(3),697-724.
MLA	Zhang, Linqiang,et al."S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis".CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY 11.3(2021):697-724.