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The p38 α  mitogen-activated protein kinase (MAPK) has been related to gluconeogenesis and lipid metabolism. However, the roles and related mechanisms of p38 α  MAPK in intestinal failure (IF)-associated liver steatosis remained poor understood. Here, our experimental evidence suggested that p38 α  MAPK significantly suppressed the fat accumulation in livers of IF patients mainly through two mechanisms. On the one hand, p38 α  MAPK increased hepatic bile acid (BA) synthesis by upregulating the expression of the rate-limiting enzyme cholesterol 7- α -hydroxylase (CYP7A1) and peroxisome proliferator-activated receptor  γ  coactivator-1 α  (PGC-1 α ), which in turn activated the transcription of the CYP7A1. On the other hand, p38 α  MAPK promoted fatty acid (FA)  β -oxidation via upregulating peroxisome proliferator-activated receptor alpha (PPAR α ) and its transcriptional target genes carnitine palmitoyltransferase 1A (CPT1A) and peroxisomal acyl-coenzyme aoxidase 1 (ACOX1). Dual luciferase assays indicated that p38 α  MAPK increased the transcription of PPAR α , PGC-1 α  and CYP7A1 by upregulating their promoters’ activities. In addition,  in vitro and in vivo  assays indicated p38 α  MAPK negatively regulates the hepatic steatosis by controlling JNK activation. In conculsion, our findings demonstrate that hepatic p38 α  MAPK functions as a negative regulator of liver steatosis in maintaining BA synthesis and FAO by antagonizing the c-Jun N-terminal kinase (JNK).

p38α MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure