Open AccessProtective Function of Mitogen‐Activated Protein Kinase Phosphatase 5 in Aging‐ and Diet‐Induced Hepatic Steatosis and Steatohepatitis
Author(s) -
Tang Peng,
Low Heng Boon,
Png Chin Wen,
Torta Federico,
Kumar Jaspal Kaur,
Lim Hwee Ying,
Zhou Yi,
Yang Henry,
Angeli Veronique,
Shabbir Asim,
Tai E. Shyong,
Flavell Richard A.,
Dong Chen,
Wenk Markus R.,
Yang Dan Yock,
Zhang Yongliang
Publication year - 2019
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1324
Subject(s) - steatohepatitis , endocrinology , steatosis , medicine , proinflammatory cytokine , nonalcoholic fatty liver disease , fatty liver , insulin resistance , biology , inflammation , protein kinase a , adipose tissue , p38 mitogen activated protein kinases , kinase , diabetes mellitus , microbiology and biotechnology , disease
Nonalcoholic fatty liver disease is currently the most common liver disease and is a leading cause of liver‐related morbidity and mortality. However, its pathogenesis remains largely unclear. We previously showed that mice deficient in mitogen‐activated protein kinase (MAPK) phosphatase 5 (MKP5) spontaneously developed insulin resistance and glucose intolerance, which are associated with visceral obesity and adipose tissue inflammation. In this study, we discovered that mice deficient in MKP5 developed more severe hepatic steatosis and steatohepatitis with age or with feeding on a high‐fat diet (HFD) compared to wild‐type (WT) mice, and this was associated with increased expression of proinflammatory cytokines and collagen genes. Increased p38 activation in MKP5 knockout (KO) liver compared to that in WT liver was detected, which contributed to increased expression of lipid droplet‐associated protein cell death‐inducing DFF45‐like effector A (CIDEA) and CIDEC/fat‐specific protein 27 but not CIDEB through activating transcription factor 2 (ATF2). In addition, MKP5 KO liver had higher peroxisome proliferator‐activated receptor gamma (PPARγ) expression compared with WT liver. On the other hand, overexpression of MKP5 or inhibition of p38 activation in hepatocytes resulted in reduced expression of PPARγ. Inhibition of p38 resulted in alleviation of hepatic steatosis in KO liver in response to HFD feeding, and this was associated with reduced expression of CIDEA, CIDEC, and proinflammatory cytokines. Conclusion: MKP5 prevents the development of nonalcoholic steatohepatitis by suppressing p38–ATF2 and p38–PPARγ to reduce hepatic lipid accumulation, inflammation, and fibrosis.