In addition, the striking inverse correlations in the NASH CRN sample of the NAFLD-increasing allele with features of metabolic syndrome risk factors further rule out an indirect effect on NAFLD via metabolic syndrome risk factors. Indeed, this inverse association may be due to the ascertainment on NAFLD: individuals with the high-risk allele of rs738409 may accumulate enough steatosis and subsequent damage to their liver to develop NAFLD at lower levels of metabolic disease than individuals who do not carry this allele. Taken together, these results suggest that risk for metabolic disease can be Akt inhibitor dissociated from fatty liver disease risk conferred

by rs738409 and that some mechanisms by which fat is deposited in liver may be related to the presence of obesity, dyslipidemia, glucose intolerance and hypertension whereas others Roxadustat mouse may be more reflective of endogenous genetic predispositions to fat accumulation in the liver. Thus, through a genetic analysis we may be able to dissociate otherwise epidemiologically related traits, and such distinctions may eventually help us to predict which treatments aimed at which pathways might be most effective for different but related metabolic diseases. We extend

previous work by showing that the G allele of rs738409 in PNPLA3 is associated with histologic steatosis as well as NASH, fibrosis and cirrhosis. Particularly striking is the association of the G allele of clonidine rs738409 with decreased likelihood of having a zone 3 centered distribution

of steatosis. Zone 3 centered steatosis is more often observed in early stages of NAFLD and is less likely to be associated with ballooned hepatocytes, Mallory-Denk bodies or advanced fibrosis than panacinar or azonal distributions of steatosis.23 Zone 3 hepatocytes are characterized by higher levels of glycolysis, liponeogenesis and ketogenesis than periportal zone 1 hepatocytes which in turn have a higher level of gluconeogenesis, urea synthesis, and bile acid and cholesterol synthesis.24-27 Although zone 3 hepatocytes may be metabolically well-suited for lipogenesis in the normal liver, in advanced disease the ability of this zone to buffer the energy overload may be overwhelmed and fat deposition throughout the liver may predominate. When the normal mechanisms that protect hepatocytes from fatty acid damage get overwhelmed, lipotoxicity, cell death and triggering of stellate cell activation ensue.28 These processes can lead to the recruitment of inflammatory cells to the liver and to the deposition of extracellular matrix, resulting in fibrosis and cirrhosis.28 Consistent with this hypothesis, the G allele of rs738409 in PNPLA3 is associated more frequently with diffuse fat deposition (not just limited to zone 3) it may promote NASH, fibrosis and cirrhosis throughout the liver.