Is the adiponectin-AMPK-mitochondrial axis involved in progression of nonalcoholic fatty liver disease?

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Non alcoholic fatty liver disease (NAFLD) is the most common form of liver disease affecting nearly a third of the population and its spectrum ranges from simple fat accumulation in the hepatocytes to non alcoholic steatohepatitis (NASH) to cirrhosis (1). Few diseases have attracted the global scientific attention that NAFLD has from such diverse fields as molecular genetics, endocrinology, sleep medicine and hepatology. From this extensive body of literature a few defining concepts have emerged. The current view on the pathogenesis of NAFLD is that a two or possibly multiple hit process results in the progression of disease (2). Excess caloric intake precedes, accompanies or is followed by insulin resistance in both the adipose tissue and skeletal muscle (3). This results in increased circulating fatty acids and their hepatocyte uptake followed by partitioning of the fatty acids to either beta oxidation or esterification to triglycerides (4). The focus of therapy has therefore been to reverse or prevent both hepatic and peripheral insulin resistance. A critical regulatory mechanism for hepatic fat accumulation has also been the reduced fatty acid oxidation and accumulation of triglycerides in the liver. β-oxidation of fatty acids occurs in both peroxisomes and mitochondria that generate acetyl CoA that needs to be oxidized via the Kreb’s cycle in the mitochondrial matrix. Mitochondrial dysfunction in NAFLD contributes to the shift of fatty acids from oxidation into the esterification and export pathways (5). Since fatty liver is intimately linked to the metabolic syndrome, disordered signaling responses have been identified in the triad of metabolically active organs comprised of the liver, adipose tissue and skeletal muscle. Alteration in insulin signaling, substrate metabolism and mitochondrial function contribute to the development and possibly progression of NAFLD. Adiponectin, an adipocytokine, is a central regulatory link between insulin resistance, disordered substrate oxidation and mitochondrial dysfunction in multiple organs (6). Adiponectin expression is highly specific to adipose tissue but has been shown in other organs including the liver and skeletal muscle (7). Circulating adiponectin exists in different isoforms: high molecular weight (HMW) and low molecular weight (LMW) multimers that bind to the cell surface receptor, T-cadherin but require additional co-receptors for intracellular signaling (7). Other circulating forms include the full length adiponectin that binds to adiponectin receptor 2 (expressed primarily in the liver) and the globular domain trimer (lacking the N terminal domain) that binds to the adiponectin receptor 1 (expressed primarily in the skeletal muscle). Ligand binding to the adiponectin receptors regulates substrate metabolism by activation of the critical energy sensors, AMPK and Sirtuins, activity of the nuclear receptor, PPARα as well as modulation of inflammatory responses (8, 9). Additional hepatic salutary effects of adiponectin include anti-inflammatory and antifibrotic effects. Despite the increasing understanding of the pathogenesis and progression of NAFLD, a number of questions remain, not the least of which are the mechanisms of progression and identifying potential molecular therapeutic targets. In the current issue, Handa et al (10) report the results of a series of very elegant in-vivo studies in the liver and adipose tissue of a murine model that replicates the spectrum of NAFLD from steatosis to NASH and complementary in-vitro studies in a murine hepatocyte cell line as well as in primary hepatocytes. They demonstrate that adiponectin depletion is a direct consequence of weight gain and plays a critical regulatory role in the development and progression of NAFLD. Their studies specifically provide answers to 2 specific questions: why does plasma adiponectin decrease with progression of NAFLD and is there a mechanistic relation between reduced adiponectin and progression of NAFLD. Using a standard murine model of insulin resistance, the Leprdb/db mice fed a high fat diet, they demonstrated hypoadiponectemia and reduced activation of AMPK and its target, acyl CoA carboxylase (ACC). Since AMPK activation is a cellular response to activate oxidative phosphorylation, reduced adiponectin acts via blunted cellular energy sensing mechanisms (9). Additionally, the authors demonstrate a novel and potentially paradigm shifting link between adiponectin and mitochondrial biogenesis (10). Interestingly, NASH was induced in mice with a liquid high fat diet with omega-6 polyunsaturated fatty acids.