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Background: Nonalcoholic fatty liver disease (NAFLD) with resulting nonalcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma (HCC) globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. Methods:A model was used to estimate NAFLD and NASH disease progression in 8 countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. Results:If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as result of urbanization and the lowest growth in Japan as result of a shrinking population.However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as result of an aging/increasing population.Conclusions: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed.If obesity and DM continue to increase at current and historical rates, both NAFLD and 4 NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.Lay summary: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) can lead to advanced liver disease, and are occurring in increasing numbers in tandem with epidemics of obesity and diabetes. A mathematical model was built to understand how the disease burden associated with NAFLD and NASH will change over time. Results suggest increasing numbers of cases of advanced liver disease and liver-related mortality in the coming years. 5 BACKGROUNDNonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease globally [1][2][3]. This condition is characterized by excess liver fat in the absence of other causes such as alcohol consumption [4,5]. Obesity, type 2 diabetes mellitus (DM) and metabolic syndrome (MetS) are consistently identified as the most important risk factors for NAFLD [4,6].In order to classify the population, NAFLD may be divided into two groups: NAFL (steatosis only) or NASH (nonalcoholic steatohepatitis), where steatosis is accompanied by inflammation and ballooning. NASH frequently progresses to liver fibrosis [7] that is the main risk factor for liver-related mortality [8]. Odds of progression to advanced liver disease, including hepatic decompensation and hepatocellular carcinoma (HCC), are higher among those with NASH compared to those with NAFL [7]. Increasing age, obesity, DM and the presence of NASH have been consistently identified as risk factors for progression to cirrhosis [6,9].There is a...

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Hepatic uptake and biliary excretion of organic anions (e.g., bile acids and bilirubin) is mediated by hepatobiliary transport systems. Defects in transporter expression and function can cause or maintain cholestasis and jaundice. Recruitment of alternative export transporters in coordination with phase I and II detoxifying pathways provides alternative pathways to counteract accumulation of potentially toxic biliary constituents in cholestasis. The genes encoding for organic anion uptake (NTCP, OATPs), canalicular export (BSEP, MRP2) and alternative basolateral export (MRP3, MRP4) in liver are regulated by a complex interacting network of hepatocyte nuclear factors (HNF1, 3, 4) and nuclear (orphan) receptors (e.g., FXR, PXR, CAR, RAR, LRH-1, SHP, GR). Bile acids, proinflammatory cytokines, hormones and drugs mediate causative and adaptive transporter changes at a transcriptional level by interacting with these nuclear factors and receptors. Unraveling the underlying regulatory mechanisms may therefore not only allow a better understanding of the molecular pathophysiology of cholestatic liver diseases but should also identify potential pharmacological strategies targeting these regulatory networks. This review is focused on general principles of transcriptional basolateral and canalicular transporter regulation in inflammation-induced cholestasis, ethinylestradiol- and pregnancy-associated cholestasis, obstructive cholestasis and liver regeneration. Moreover, the potential therapeutic role of nuclear receptor agonists for the management of liver diseases is highlighted.