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Publication
Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates
glucose metabolism and energy homeostasis.
Authors Lawan A, Zhang L, Gatzke F, Min K, Jurczak MJ, Al-Mutairi M, Richter P, Camporez
JP, Couvillon A, Pesta D, Roth Flach RJ, Shulman GI, Bennett AM
Submitted By Submitted Externally on 11/10/2015
Status Published
Journal Molecular and cellular biology
Year 2015
Date Published
Volume : Pages 35 : 26 - 40
PubMed Reference 25312648
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.




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