Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.
Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease.
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Shuai
S
Chen
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yujia
Y
Kang
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yan
Y
Sun
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yanhong
Y
Zhong
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yanli
Y
Li
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Lijuan
L
Deng
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Jin
J
Tao
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yang
Y
Li
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yingpu
Y
Tian
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Yinan
Y
Zhao
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Jianghong
J
Cheng
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China.
Wenjie
W
Liu
Department of Pathology, and Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA zhongxian@xmu.edu.cn gfeng@ucsd.edu.
Gen-Sheng
GS
Feng
School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian 361005, China zhongxian@xmu.edu.cn gfeng@ucsd.edu.
Zhongxian
Z
Lu
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology*; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D017353:Gene Deletion; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D019301:Oleic Acid; D010750:Phosphoproteins / Q000378:metabolism*; D020011:Protective Agents / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C490897:Gab1 protein, mouse; C490894:Gab2 protein, mouse; C495949:Grb2 protein, mouse; D008055:Lipids; D010750:Phosphoproteins; D020011:Protective Agents; D019301:Oleic Acid; D000431:Ethanol; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
alcoholic fatty liver disease; disease-associated protein; knockout mouse; non-alcoholic fatty liver disease; therapeutic target