By linear regression, levels of deoxycholic acid (DCA) and glycine conjugated DCA paralleled the increase in adiponectin (DCA: r = 0.51, P < 0.01, G-DCA: r = 0.49, P < 0.01), but not cholic acid (CA), chenodeoxycholic acid (CDCA), or ursodeoxycholic acid (UDCA). In a final experiment, to test the role of bile acids on adiponectin expression we treated learn more differentiated 3T3-L1 adipocytes with fexaramine

(FXR agonist) or taurolithocholic acid (TGR-5 agonist) and examined the cell culture supernatant for adiponectin protein. We found that both fexaramine and taurolithocholic acid increased adiponectin protein secretion greater than 10-fold (Fig. 3). These data suggest that bile acids act directly to regulate adiponectin synthesis in adipocytes. One of the most intriguing and unanswered questions in clinical hepatology concerns the observation that liver fat loss often accompanies advanced fibrosis and cirrhosis, something that delayed the linkage of NASH to cryptogenic cirrhosis for many years. In this study we show for the first time that alterations in serum adiponectin may provide an explanation for this phenomenon and suggest a novel mechanism by which this might occur (Fig. 4). In well-characterized patients with biopsy

proven NASH, we show that (1) circulating adiponectin levels have an inverse correlation with hepatic fat content in those with advanced disease; (2) as hepatic fat declines with advanced fibrosis, adiponectin levels progressively rise, independent of its usual metabolic associations, viz. insulin resistance, leptin, ROCK inhibitor BMI, and WHR; (3) elevated serum adiponectin is significantly and independently associated with almost complete hepatic fat loss, so-called “burnt-out” NASH, even when controlled for patient age and markers of liver synthetic dysfunction; (4) circulating adiponectin in advanced NASH is associated with activation of its downstream signaling in the liver; (5) bile acids in late-stage NASH that are ligands for the bile acid receptors FXR and TGR527 are elevated in patients; and finally (6) that

this elevation in circulating bile acids may be responsible for the secretion of adiponectin by adipocytes in advanced liver disease (Fig 4). Adiponectin is a key player in the pathogenesis of NASH-related Urease steatosis, with an intimate association between hypoadiponectinemia, increasing steatosis grade, and the transformation from simple steatosis to NASH.16, 28 Acting predominantly by way of the hepatic adiponectin receptor 2 (AdipoR2), elevated levels of adiponectin are profoundly antisteatotic, an effect mediated by stimulation of PPAR-α with an increase in fatty acid β-oxidation, and inhibition of fatty acid synthesis by way of SREBP-1c.13 It is now well established that adiponectin is elevated in advanced liver disease and cirrhosis of any cause, although most evidence exists for viral, autoimmune, cholestatic, and alcohol-related disease.