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 (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.

Protective and Detrimental Roles of p38α Mitogen‐Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease

“…This is consistent with a recent report that inhibition of p38 slightly reduced PPARγ and its target genes in HFD‐fed C57BL/6J (WT) mice, although it markedly inhibited these genes in HFD‐fed MAPK phosphatase 5 knockout mice that were associated with severe steatosis. ( 31 ) Collectively, p38a Hep‐/‐ mice are more susceptible to HFD‐induced steatosis because of the reduced hepatic expression of PPARα, not lipogenic genes, and subsequent reduced FA oxidation. Therefore, we further examined PPARα phosphorylation, which stimulates its ligand‐induced transactivation, and its own expression.…”

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

“…A more recent study showed that DUSP12, which plays an important role in brown adipocyte differentiation, physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on p38α/β in order to reducelipogenesis and to suppress lipid accumulation in livers of high-fat fed mice [167]. Similar to DUSP12, DUSP14, DUSP26 and MKP-5 suppress the development of hepatic steatosis by inhibiting p38s [167][168][169][170]. Both DUSP14 and DUSP26 directly bind and dephosphorylate TAK1 kinase, which results in the inhibition of TAK1 and its downstream targets JNKs and p38s [168,169].…”

“…Both DUSP14 and DUSP26 directly bind and dephosphorylate TAK1 kinase, which results in the inhibition of TAK1 and its downstream targets JNKs and p38s [168,169]. MKP-5 prevents the development of hepatic steatosis by suppressing p38-ATF2 and p38-PPARγ signaling axis to reduce hepatic lipid accumulation [170]. Finally, F-prostanoid receptor (FP) activation through the CaMKIIγ/p38/FOXO1 signaling pathway was demonstrated to facilitate hepatic gluconeogenesis in mice by upregulating gluconeogenic genes under both fasting and diabetic conditions [171].…”

Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer

“…Liver-specific deficiency of MKP1 results in increased p38 and JNK MAPK activity in mouse models [154]. This is also seen in MKP5 deficient mice [155]. The role of p38 MAPK signalling in regulating metabolic responses to stress in the liver is controversial; however, these data suggest that MKP1 may reduce the p38 and JNK MAPK-mediated transcription of gluconeogenic genes, as well as p38 MAPK-mediated phosphorylation of CREB (cyclic AMP responsive element binding protein), which also promotes gluconeogenesis through PPARγ [154], all of which may lead to increased lipogenesis in the liver.…”