Coordinate control of metabolic flux with liver energy status by AMPK in vivo

Abstract

AMP-activated protein kinase (AMPK) is a serine-threonine kinase that exerts control over mediators of metabolic flux. The structure of AMPK permits the sensing of changes in energy status. The dissertation examines the necessity of AMPK for the metabolic response to physiological, pharmaceutical (AICAR) and pathophysiological energy stress in the liver. Mice with a liver-specific deletion of both AMPKα catalytic subunits were used to investigate these aims. The <i>physiology</i> of liver AMPK was tested by examining metabolic regulation during fasts of different durations. The results show that AMPK is crucial for coordinating <i>in vivo</i> substrate flux with energy homeostasis in the liver. AMPK deletion impairs mitochondrial function and elevates BCAA/BCKA-related metabolites. Fasting-mediated deficits in hepatic energy state are exacerbated in the absence of AMPK, despite an elevation in citrate synthase flux. These results demonstrate that AMPK deletion leads to defective coupling of cofactor synthesis and oxidative phosphorylation in the liver. Some <i>pharmaceutical</i> agents used therapeutically to control diabetes also reduce energy state and activate AMPK. The deleterious effect of AICAR on energy state is exacerbated in the absence of AMPK and corresponds to a relative elevation in liver triglycerides. AMPK is dispensable, however, for the acute inhibition of endogenous glucose production by AICAR. The <i>pathogenesis</i> of overnutrition (high-fat feeding) elicits aberrant liver energy homeostasis. The role of AMPK signaling in the reversal of fatty liver by regular exercise was tested. Liver triglycerides drop significantly following 10wks of voluntary exercise in high fat-fed mice, independent of hepatic AMPK. In the absence of AMPK, exercise fails to improve deficits in hepatic ATP, which corresponds to an accumulation of short-chain acylcarnitines in high fat-feeding. Collectively, this dissertation demonstrates that hepatic AMPK preserves energy state during physiological, pharmacological, and pathological states by coordinating substrate availability and oxidative capacity with ATP production in the liver.