As a consequence of the worldwide epidemic of diabesity, the prevalence of nonalcoholic fatty liver disease (NAFLD) is continuously rising.1 According to current concepts, the subset of patients with nonalcoholic steatohepatitis (NASH), histologically characterized by hepatocyte ballooning, inflammation, www.selleckchem.com/products/ldk378.html fibrosis, in addition to steatosis,2 are at significant risk for adverse hepatic outcomes due to cirrhosis and hepatocellular carcinoma.3 Interestingly, patients with advanced NASH and related cirrhosis may no longer display pronounced hepatic lipid accumulation,

a constellation known as “burnt-out NASH.” This may have contributed to underestimation of this etiology since such patients may have frequently been classified as “cryptogenic” in the past. While many possible explanations such as diversion of insulin and nutrients from the liver due to portal hypertension Sorafenib in vitro and the general catabolic state in liver cirrhosis have been brought forward,4 the molecular mechanisms explaining this paradox have remained poorly understood. In this issue,

Van der Poorten et al.5 have now addressed this important question in a series of metabolically and histologically well-characterized NASH patients and made the key observation that raising serum adiponectin levels were inversely correlated with hepatic fat content in advanced NASH while increases of certain bile acid (BA) species may contribute to this phenomenon. Adiponectin is a 247 amino acid protein secreted by adipocytes belonging to the collagen superfamily and forming low and high molecular weight complexes in blood, the latter being the most biologically active with a key role in glucose and lipid metabolism.6 In liver, adiponectin signals by way of two distinct receptors, adipoRI and adipoRII,7 which have distinct biological roles: RI

controls AMP-activated protein kinase (AMPK) activation responsible for the regulation of de novo lipogenesis and fatty acid (FA) oxidation, while RII controls peroxisome proliferator activated receptor alpha (PPARα) and thereby counteracts Unoprostone inflammation and oxidative stress (Fig. 1).8 In addition, using high-throughput RNA sequencing in mouse, adiponectin was shown to regulate glycolysis, cholesterol, triglycerides content, and FA synthesis by way of hepatocyte nuclear factor 4 alpha (HNF4α) (Fig. 1).9 Therefore, studies on the role of adiponectin in advanced NASH patients have great potential to reveal new molecular mechanisms responsible for progression from NASH to cirrhosis. The current study by Van der Poorten et al.5 established that adiponectin levels were paradoxically rising while hepatic fat declined. Notably, high serum adiponectin was the strongest predictor of burnt-out NASH.