Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism

Abstract

The mitogen-activated protein kinases (MAPKs) participate in a multitude of processes that control hepatic metabolism. The liver regulates glucose and lipid metabolism and under pathophysiological conditions, such as obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease these processes become dysfunctional. Stress responses activate the hepatic MAPKs which, is thought to impair insulin action and lipid metabolism. The MAPKs also activate the MAPK phosphatases which, oppose their actions. How the MAPK/MKP balance is controlled in liver metabolism and how perturbations in these activities contribute to metabolic disease remains unclear. A discussion of recent insights into the MAPK/MKP signaling role in hepatic metabolic function and disease will be the focus of this review.

Dual‐Specificity Phosphatase 9 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through ASK1 Suppression

“…Mechanistically, Dusp9 protects against NASH mainly through restraining ASK1–JNK/p38 signaling. In the liver, JNK/p38 signaling plays a central role in processes that control hepatic metabolism . In brief, JNK1 directly perturbs hepatic lipid metabolism by regulating PPARα and facilitates IR by promoting serine phosphorylation of IRS1 in hepatocytes .…”

“…Compared to these regulators, Dusp9 belongs to the MAPK phosphatase (MKP) family. MAPK hyperactivation in turn activates the MKPs to oppose their action, which forms a feedback regulation loop . Thus, targeting Dusp9–ASK1 signaling, a physiological regulation loop, may provide an effective and reliable strategy for NASH treatment.…”

“…In the liver, JNK/p38 signaling plays a central role in processes that control hepatic metabolism. (23) In brief, JNK1 directly perturbs hepatic lipid metabolism by regulating PPARα (24) and facilitates IR by promoting serine phosphorylation of IRS1 in hepatocytes. (25) Moreover, JNK is closely involved in the hyperactivated inflammatory response in liver.…”

Inhibition of Adenosine Monophosphate–Activated Protein Kinase–3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance

“…Furthermore, in addition to increased lipogenic and gluconeogenic genes, HMGCR KI mice exhibited enhanced macrophage infiltration and elevated proinflammatory cytokine Il6 expression. In NAFLD subjects, both nuclear factor kappa B and mitogen‐activated protein kinase pathways were found to be enhanced and have a direct correlation with hepatic inflammation and fibrosis . Thus, it is possible that these pathways may also indirectly mediate some of the phenotypes besides the up‐regulation of cholesterol synthesis in HMGCR KI mice…”

“…In NAFLD subjects, both nuclear factor kappa B and mitogen-activated protein kinase pathways were found to be enhanced and have a direct correlation with hepatic inflammation and fibrosis. (45,46) Thus, it is possible that these pathways may also indirectly mediate some of the phenotypes besides the up-regulation of cholesterol synthesis in HMGCR KI mice Recently, Woods et al (47) reported that mice expressing a constitutively active form of AMPK (γ1-Asp316Ala) in the liver were protected from developing hepatic steatosis on a high-fructose diet. These mice had essentially the reciprocal phenotype to the HMGCR KI mice that develop steatosis on a high-carbohydrate diet.…”