Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders

Abstract

It is now becoming evident that the liver has an important role in the control of whole body metabolism of energy nutrients. In this review, we focus on recent findings showing that AMP-activated protein kinase (AMPK) plays a major role in the control of hepatic metabolism. AMPK integrates nutritional and hormonal signals to promote energy balance by switching on catabolic pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation and inhibition of lipogenesis, glucose production and protein synthesis. Medical interest in the AMPK system has recently increased with the demonstration that AMPK could mediate some of the effects of the fat cell-derived adiponectin and the antidiabetic drugs metformin and thiazolidinediones. These findings reinforce the idea that pharmacological activation of AMPK may provide, through signalling and metabolic and gene expression effects, a new strategy for the management of metabolic hepatic disorders linked to type 2 diabetes and obesity.

Figure 1. Regulation of lipid metabolism by hepatic AMPK

Activation of AMPK leads to the inhibition of cholesterol synthesis by phosphorylation of HMG-CoA reductase. By inhibiting ACC and activating MCD, AMPK increases fatty acid oxidation via the regulation of levels of malonyl-CoA, which is both a critical precursor for biosynthesis of fatty acids and a potent inhibitor of CPT-1, the enzyme that controls the transfer of long-chain fatty acyl-CoA into the mitochondria. AMPK inhibits also GPAT, the first committed enzyme in glycerolipid synthesis. The net resulting effect of AMPK activation is to inhibit energy-consuming lipogenic pathways (fatty acid, triglyceride and sterol synthesis) in favour of fatty acid oxidation. FA-CoA: fatty acyl-CoA.

Figure 2. Diagrammatic representation of signalling involved in the regulation of the mTOR/p70S6K pathway by AMPK

A, both insulin and amino acids stimulate the mTOR/p70S6K pathway to promote protein synthesis. Insulin, by activating the phosphatidylinositol-3-kinase/protein kinase B pathway, inhibits TSC2, and so, via the activation of Rheb, induces mTOR activation. On the other hand, the pathway used by amino acids like leucine or glutamine to activate the mTOR pathway is still not well defined. Once activated, mTOR, with the participation of Raptor, is able to phosphorylate 4EBP-1 and p70S6K. B, activated AMPK is able to phosphorylate and activate both TSC2 and eEF2K. Moreover, AMPK can inactivate directly mTOR. GEF: guanylate exchange factor.

Figure 3. Effect of dietary PUFAs on L-PK and ChREBP gene expression and ChREBP localization in livers of AMPKα1α2_LS^−/− mice

A, quantitative RT-PCR analysis of L-PK and ChREBP gene expression from livers of 24 h-fasted mice (F) and mice re-fed for 18 h with a high carbohydrate diet (HCHO) supplemented or not with PUFAs (PUFA) performed in control (filled bars) and AMPKα1α2_LS^−/− (open bars) mice. Results are means ± s.e.m.; n = 3/group. *Significantly different from mice re-fed with HCHO diet for 18 h (P < 0.005). B, cytosolic and nuclear ChREBP content from livers of 24 h-fasted control and AMPKα1α2_LS^−/− mice re-fed for 18 h upon HCHO diet supplemented or not with PUFAs. Expression of AMPKα catalytic subunits has been measured by using anti-pan-AMPKα antibodies. β-Actin protein levels are presented as loading control. A representative Western blot is shown; n = 3/group.

Figure 4. Transcriptional control of gluconeogenesis by TORC2 and AMPK

A, in response to fasting, the cAMP-responsive CREB coactivator TORC2 controls the gluconeogenic programme in liver via its nuclear translocation and association with CREB transcription factor, driving the expression of the PGC1α coactivator. Expression of the coactivator PGC-1α in turn drives the transcription of key gluconeogenic enzymes such as PEPCK and G6Pase in association with the transcription factor HNF4α and the forkhead family activator FoxO1. B, activity of TORC2 is controlled by AMPK and AMPK-related kinase SIK phosphorylation, which determines whether TORC2 becomes localized in the nucleus. Phosphorylated TORC2 is sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Moreover, AMPK can also control gluconeogenic gene transcription by regulating stability or degradation of HNF4α and FoxO1 transcription factors.