Crosstalk of 5′-Monophosphate-Activated Protein Kinase (AMPK) with Extracellular and Intracellular Signaling Pathways in the Regulation of Nutrient Metabolism and Cell Survival in the Liver

Abstract

As a key regulator of nutrient metabolism and cell survival, 5′-monophosphate-activated protein kinase (AMPK) is a very promising drug target for treating metabolic diseases, nonalcoholic fatty liver disease, and cancer. However, recent studies from the use of AMPK knockout mice as well as genetic and chemical modulators of AMPK have generated conflicting reports regarding the roles of AMPK in the regulation of hepatic lipid metabolism, fulminant hepatitis, and cholestatic liver injury. The purpose of this review is to summarize recent knowledge regarding how AMPK crosstalks with diverse extracellular and intracellular signaling pathways to regulate hepatic nutrient metabolism and cell survival, in an effort to help better understand the potential underlying mechanisms of these recent controversies. AMPK directly regulates a group of key transcription factors that are essential for nutrient metabolism and/or cell survival. The effects of AMPK activation on PPARα, LXRα, HNF4α, FXR, Nrf2, and JNK appear to be dependent on cellular context or gene targets. The most widely used AMPK activators (AICAR and metformin) and AMPK inhibitor (compound C) have important AMPK-independent activities that may confound data interpretation. Mutation/deletion of different AMPK subunits may have different biological activities that contribute to their distinct effects on hepatic gene expression and lipid metabolism. Future studies using more specific and physiologically relevant genetic/chemical modulators of AMPK will help elucidate the exact roles of AMPK in the regulation of lipid metabolism, fulminant hepatitis, and cholestatic liver injury.