2. Academic Validation
  3. Hepatic P38 Activation Modulates Systemic Metabolism Through Fgf21-Mediated Interorgan Communication

Hepatic P38 Activation Modulates Systemic Metabolism Through Fgf21-Mediated Interorgan Communication

  • Diabetes. 2021 Oct 21;db210240. doi: 10.2337/db21-0240.
Wei Liu 1,  Chao Sun 1,  Ying Yan 1,  Hongchao Cao 1,  Zhoumin Niu 1,  Siyi Shen 1,  Shengnan Liu 1,  Yuting Wu 1,  Yan Li 2,  Lijian Hui 3,  Yuying Li 1,  Lin Zhao 4,  Cheng Hu 5,  Qiurong Ding 1,  Jingjing Jiang 6,  Hao Ying 7 8 9
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of 1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Sciences; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 2 State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.
  • 3 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 6 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; jiang.jingjing@zs-hospital.sh.cn yinghao@sibs.ac.cn.
  • 7 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of 1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Sciences; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; jiang.jingjing@zs-hospital.sh.cn yinghao@sibs.ac.cn.
  • 8 Innovation Center for Intervention of Chronic Disease and Promotion of Health.
  • 9 Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
PMID: 34675006 DOI: 10.2337/db21-0240
Abstract

The mechanisms underlying the pathogenesis of steatosis and Insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and Insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor β-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expffression are increased, β-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38α, FGF21, and β-Klotho in the pathogenesis of nonalcoholic fatty liver disease.

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