Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Cell Biol. 2015 Jan;35(1):26-40. doi: 10.1128/MCB.00503-14. Epub 2014 Oct 13.

Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis.

Author information

  • 1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 2Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 3Cell Signaling Technology Incorporated, Danvers, Massachusetts, USA.
  • 4Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
  • 5Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA anton.bennett@yale.edu.

Abstract

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

PMID:
25312648
PMCID:
PMC4295383
DOI:
10.1128/MCB.00503-14
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center