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The PPAR?-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.

ABSTRACT: The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?). Therefore, JNK causes decreased expression of PPAR? target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPAR? target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPAR?-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.

SUBMITTER: Vernia S

PROVIDER: S-EPMC4156535 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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The PPARα-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.

Vernia Santiago S Cavanagh-Kyros Julie J Garcia-Haro Luisa L Sabio Guadalupe G Barrett Tamera T Jung Dae Young DY Kim Jason K JK Xu Jia J Shulha Hennady P HP Garber Manuel M Gao Guangping G Davis Roger J RJ

Cell metabolism 20140717 3

The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). Therefore, JNK causes decreased expression of PPARα target genes that increase fatty acid oxidation ...[more]

PMID: 25043817

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Project description:Background & aimsThe prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.MethodsThe clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.ResultsSerum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.ConclusionsLiver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.

Dataset Information

The PPAR?-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.

Publications

The PPARα-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.

Similar Datasets

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