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Protective Function of Mitogen-Activated Protein Kinase Phosphatase 5 in Aging- and Diet-Induced Hepatic Steatosis and Steatohepatitis.

ABSTRACT: 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 (PPAR?) expression compared with WT liver. On the other hand, overexpression of MKP5 or inhibition of p38 activation in hepatocytes resulted in reduced expression of PPAR?. 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-PPAR? to reduce hepatic lipid accumulation, inflammation, and fibrosis.

SUBMITTER: Tang P

PROVIDER: S-EPMC6546013 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Protective Function of Mitogen-Activated Protein Kinase Phosphatase 5 in Aging- and Diet-Induced Hepatic Steatosis and Steatohepatitis.

Tang Peng P Low Heng Boon HB Png Chin Wen CW Torta Federico F Kumar Jaspal Kaur JK Lim Hwee Ying HY Zhou Yi Y Yang Henry H Angeli Veronique V Shabbir Asim A Tai E Shyong ES Flavell Richard A RA Dong Chen C Wenk Markus R MR Yang Dan Yock DY Zhang Yongliang Y

Hepatology communications 20190301 6

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 de ...[more]

PMID: 31168510

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Project description:Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH.ConclusionIncreased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431).

Dataset Information

Protective Function of Mitogen-Activated Protein Kinase Phosphatase 5 in Aging- and Diet-Induced Hepatic Steatosis and Steatohepatitis.

Publications

Protective Function of Mitogen-Activated Protein Kinase Phosphatase 5 in Aging- and Diet-Induced Hepatic Steatosis and Steatohepatitis.

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