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

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