Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease.
The status of the GP130-STAT3 signaling pathway in humans with nonalcoholic fatty liver disease (NAFLD) and its relevance to disease pathogenesis are unknown. The expression of the gp130-STAT3 axis and gp130 cytokine receptors were studied in subjects with varying phenotypes of NAFLD including nonalcoholic steatohepatitis (NASH) and compared with lean and weight-matched controls without NAFLD. Gp130 and its downstream signaling element (Tyk2 and STAT3) expression were inhibited in obese controls whereas they were increased in NAFLD. IL-6 levels were increased in NASH and correlated with gp130 expression (P < 0.01). Palmitate inhibited gp130-STAT3 expression and signaling. IL-6 and palmitate inhibited hepatic insulin signaling via STAT3-dependent and independent mechanisms, respectively. STAT3 overexpression reversed palmitate-induced lipotoxicity by increasing autophagy (ATG7) and decreasing endoplasmic reticulum stress. These data demonstrate that the STAT3 pathway is activated in NAFLD and can worsen insulin resistance while protecting against other lipotoxic mechanisms of disease pathogenesis.
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and.
Hae-Ki
HK
Min
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and.
Faridoddin
F
Mirshahi
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and.
Aurora
A
Verdianelli
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and.
Tommy
T
Pacana
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and.
Vaishali
V
Patel
Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Chungbuk, Republic of Korea.
Chun-Geon
CG
Park
Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Chungbuk, Republic of Korea.
Aejin
A
Choi
Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Chungbuk, Republic of Korea.
Jeong-Hoon
JH
Lee
Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Chungbuk, Republic of Korea.
Chung-Berm
CB
Park
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and.
Shunlin
S
Ren
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; and asanyal@mcvh-vcu.edu.
Arun J
AJ
Sanyal
D000328:Adult; D000368:Aged; D000071193:Autophagy-Related Protein 7; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
C508600:IL6 protein, human; C494199:IL6ST protein, human; D007328:Insulin; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D019308:Palmitic Acid; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes
IL-6; NAFLD; NASH; STAT3; autophagy; gp130; insulin resistance; palmitate