Thrombospondin 1 improves hepatic steatosis in diet-induced insulin-resistant mice and is associated with hepatic fat content in humans
Jinyun Bai,
Mingfeng Xia,
Yaqian Xue,
Fengguang Ma,
Aoyuan Cui,
Yixuan Sun,
Yamei Han,
Xi Xu,
Feifei Zhang,
Zhimin Hu,
Zhengshuai Liu,
Yuxiao Liu,
Genxiang Cai,
Weitong Su,
Xiaoyang Sun,
Haifu Wu,
Hongmei Yan,
Xinxia Chang,
Xiqi Hu,
Hua Bian,
Pu Xia,
Jing Gao,
Yu Li,
Xin Gao
Affiliations
Jinyun Bai
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Mingfeng Xia
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Yaqian Xue
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Fengguang Ma
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Aoyuan Cui
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Yixuan Sun
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Yamei Han
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Xi Xu
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Feifei Zhang
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Zhimin Hu
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Zhengshuai Liu
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Yuxiao Liu
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Genxiang Cai
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Weitong Su
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Xiaoyang Sun
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Haifu Wu
Metabolic and Bariatric Surgery of Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
Hongmei Yan
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Xinxia Chang
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Xiqi Hu
Department of Pathology, Medical College, Fudan University, Shanghai, China
Hua Bian
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Pu Xia
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China
Jing Gao
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Yu Li
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Corresponding author at: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Xin Gao
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Fudan Institute for Metabolic Diseases, Shanghai, China; Corresponding author at: Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
Background: Nonalcoholic fatty liver disease (NAFLD) is associated with altered production of secreted proteins. Increased understanding of secreted proteins could lead to improved prediction and treatment of NAFLD. Here, we aimed to discover novel secreted proteins in humans that are associated with hepatic fat content using unbiased proteomic profiling strategy, and how the identified Thbs1 modulates lipid metabolism and hepatic steatosis. Method: NAFLD patients were enrolled and treated with lifestyle intervention. Patients who underwent liver biopsy were enrolled for analyzing the correlation between circulating Thbs1 and liver steatosis. Mice were fed on high-fat, high-sucrose diet and treated with recombinant Thbs1. Primary hepatocytes isolated from CD36 knockout (CD36-/-) mice and their wild-type littermates (controls) were treated with glucose plus insulin for 24 h together with or without recombinant Thbs1. Finding: Serum Thbs1 levels are increased in participants with NAFLD and positively associated with liver steatosis grades. Improvement of liver steatosis after lifestyle intervention was accompanied with significant reduction of serum Thbs1 levels. Pharmacological administration of recombinant human Thbs1 attenuates hepatic steatosis in diet-induced obese mice. Treatment with Thbs1 protein or stably overexpression of Thbs1 causes a significant reduction of lipid accumulation in primary hepatocytes or HepG2 cells exposed to high glucose plus insulin, suggesting that Thbs1 regulates lipid metabolism in a hepatocyte-autonomous manner. Mechanistically, Thbs1 inhibits cleavage and processing of SREBP-1, leading to a reduction of target lipogenic gene expression and hepatic steatosis. Inhibitory effects of Thbs1 on lipogenesis and triglyceride accumulation are abrogated in CD36 deficient primary hepatocytes exposed to high glucose plus insulin. Interestingly, beneficial effects of Thbs1 on lipid accumulation are observed in primary hepatocytes treated with a Thbs1 nonapeptide mimetic ABT-526. Interpretation: Thbs1 is a biomarker for NAFLD in humans, and pharmacological and genetic approaches for the modulation of Thbs1 activity may have the therapeutic potential for treating hepatic steatosis. Fund: A full list of funding bodies that contributed to this study can be found in the Funding Sources section.
