AMP‐activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives

Abstract

As the liver is central in the maintenance of glucose homeostasis and energy storage, knowledge of the physiology as well as physiopathology of hepatic energy metabolism is a prerequisite to our understanding of whole-body metabolism. Hepatic fuel metabolism changes considerably depending on physiological circumstances (fed vs. fasted state). In consequence, hepatic carbohydrate, lipid and protein synthesis/utilization are tightly regulated according to needs. Fatty liver and hepatic insulin resistance (both frequently associated with the metabolic syndrome) or increased hepatic glucose production (as observed in type 2 diabetes) resulted from alterations in substrates oxidation/storage balance in the liver. Because AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor, it is important to gain understanding of the mechanism by which hepatic AMPK coordinates hepatic energy metabolism. AMPK has been implicated as a key regulator of physiological energy dynamics by limiting anabolic pathways (to prevent further ATP consumption) and by facilitating catabolic pathways (to increase ATP generation). Activation of hepatic AMPK leads to increased fatty acid oxidation and simultaneously inhibition of hepatic lipogenesis, cholesterol synthesis and glucose production. In addition to a short-term effect on specific enzymes, AMPK also modulates the transcription of genes involved in lipogenesis and mitochondrial biogenesis. The identification of AMPK targets in hepatic metabolism should be useful in developing treatments to reverse metabolic abnormalities of type 2 diabetes and the metabolic syndrome.

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

“…The adenosine monophosphate analogue 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) activates AMPdependent protein kinase (AMPK), which is a key regulator of energy metabolism and thus a potential target for treatment of obesity-related complications [4,5]. Evidence from experimental models has shown that AICAR may attenuate metabolic [6][7][8], hepatic [9][10][11] and renal pathophysiology [12][13][14][15].…”

Bidirectional regulation of adenosine 5′‐monophosphate–activated protein kinase activity by berberine and metformin in response to changes in ambient glucose concentration

“…AMPK has been identified as a master regulator of cellular energy status and plays a crucial role against energy‐restricted conditions 22. Among them, the glucose deprivation is one of the most important factors to regulate the AMPK activity 23.…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…In human adipocytes, b-adrenergic stimulation of lipolysis was found to be down-regulated by concomitant activation of AMPK through TZDs (Bourron et al 2010). Overall, acute AMPK activation in adipose tissue leads to an inhibition of both lipogenesis and lipolysis, whereas it increases fatty acid oxidation and glucose transport (Viollet et al 2009;Daval et al 2006). It seems counter-intuitive (Daval et al 2006) that AMPK inhibits lipolysis, although it is itself activated in situations of increased lipolysis.…”

“…Muscle AMPK is involved in the coordinated transcription of genes important for lipid and glucose metabolism during exercise and for acute control of metabolic fluxes, namely the switch from carbohydrate to lipid oxidation (Hardie 2008;Zhang et al 2009;McGee and Hargreaves 2010;Canto et al 2010;Viollet et al 2009). Thus, AMPK is activated by muscle contraction, which depletes ATP leading to an increase in the AMP/ATP ratio.…”