Novel pathways in the pathogenesis and pathophysiology of NAFLD in Hispanics

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Project Summary Non-alcoholic fatty liver disease (NAFLD/NASH), the most common of liver pathologies in the US, varies widely among races/ethnicities with higher rates in Hispanics than non-Hispanic Whites, making this disease one of the most profound health disparities. In preliminary data, we have confirmed this health disparity using the NHANES 1988-1994 data base. In this proposal investigators from three institutions, Ohio University, Charles R. Drew University and the University of Florida are collaborating to uncover the etiology of this health disparity by delineating its epidemiological, cellular and molecular underpinnings. Obese subjects with NAFLD and insulin resistance exhibit a lower level of hepatic CEACAM1, a protein that limits hepatic steatosis by promoting hepatic insulin clearance and subsequently, preventing hyperinsulinemia-driven lipogenesis, and by mediating a negative effect of acute release of insulin on fatty acid synthase activity in liver. Reduction of CEACAM1 expression is mediated by lipolysis-derived fatty acids activation of PPAR alpha. In preliminary RNASeq data analysis, we show that the mRNA levels of CEACAM1 are significantly lower in the livers of Hispanic than non- Hispanic White liver donors, in parallel to lower expression of PNPLA3 lipase that harbors a well-documented mutation in NAFLD/NASH patients and Hispanics. We also show lower levels of CIDEC/FSP27, a protein that interacts with the adipose triglyceride lipase to prevent lipolysis from adipoyctes, in the abdominal fat tissue (AT) of Hispanics versus non-Hispanic Whites undergoing bariatric surgery. Given that CIDEC/FSP27 is reduced in the abdominal AT of obese subjects, and because its mutation is associated with increased lipolysis in humans, we hypothesize that Hispanics exhibit higher hepatic de novo lipogenesis and steatosis compared to non- Hispanic Whites, and that this is mediated by reduced hepatic CEACAM1 expression that results from excess free fatty acid flux during lipolysis, which is in turn caused by reduction of CIDEC level in abdominal adipose tissue. To test this hypothesis, we will in Aim 1, use NHANES databases to identify the epidemiological underpinnings of this health disparity. In Aim 2, we will delineate the role of the loss of CIDEC in AT in hepatic steatosis in Hispanics. In Aim 3, we will investigate whether the loss of CIDEC in AT causes a decrease in hepatic CEACAM1 in Hispanics in parallel to hepatic steatosis. Our approach is designed to study the adipose tissue-liver cross-talk that plays a critical role in NAFLD disparity. A strength of this proposal is an interdisciplinary collaboration between Drs. Ali Zarrinpar (liver transplant and hepatobiliary surgeon), Sonia M. Najjar (fatty liver disease and lipid metabolism), Vishwajeet Puri (adipose biology and lipid metabolism) and Theodore Friedman (hepatic steatosis and Health disparity in metabolic disease). As is clear from the strong preliminary data, these scientists have productively collaborated on a proposal that will delineate the novel pathways in the pathogenesis of NAFLD in Hispanics and lead to successful treatments to reduce this remarkable health disparity.