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p38α MAPK antagonizing JNK to control the hepatic fat accumulation in pediatric patients onset intestinal failure.
- Source :
-
Cell death & disease [Cell Death Dis] 2017 Oct 12; Vol. 8 (10), pp. e3110. Date of Electronic Publication: 2017 Oct 12. - Publication Year :
- 2017
-
Abstract
- The p38α mitogen-activated protein kinase (MAPK) has been related to gluconeogenesis and lipid metabolism. However, the roles and related mechanisms of p38α MAPK in intestinal failure (IF)-associated liver steatosis remained poor understood. Here, our experimental evidence suggested that p38α MAPK significantly suppressed the fat accumulation in livers of IF patients mainly through two mechanisms. On the one hand, p38α 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-1α (PGC-1α), which in turn activated the transcription of the CYP7A1. On the other hand, p38α MAPK promoted fatty acid (FA) β-oxidation via upregulating peroxisome proliferator-activated receptor alpha (PPARα) and its transcriptional target genes carnitine palmitoyltransferase 1A (CPT1A) and peroxisomal acyl-coenzyme aoxidase 1 (ACOX1). Dual luciferase assays indicated that p38α MAPK increased the transcription of PPARα, PGC-1α and CYP7A1 by upregulating their promoters' activities. In addition, in vitro and in vivo assays indicated p38α MAPK negatively regulates the hepatic steatosis by controlling JNK activation. In conculsion, our findings demonstrate that hepatic p38α MAPK functions as a negative regulator of liver steatosis in maintaining BA synthesis and FAO by antagonizing the c-Jun N-terminal kinase (JNK).
- Subjects :
- Acyl-CoA Oxidase biosynthesis
Animals
Bile Acids and Salts biosynthesis
Carnitine O-Palmitoyltransferase biosynthesis
Cells, Cultured
Cholesterol 7-alpha-Hydroxylase biosynthesis
Cholesterol 7-alpha-Hydroxylase genetics
Disease Models, Animal
Humans
Infant
JNK Mitogen-Activated Protein Kinases metabolism
Lipid Metabolism
Liver pathology
PPAR alpha biosynthesis
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha biosynthesis
Promoter Regions, Genetic
RNA Interference
RNA, Small Interfering genetics
Rats, Sprague-Dawley
Transcription, Genetic genetics
Transcriptional Activation
Fatty Acids metabolism
Fatty Liver pathology
Intestines pathology
JNK Mitogen-Activated Protein Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 8
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 29022907
- Full Text :
- https://doi.org/10.1038/cddis.2017.523