Novel pathways in the pathogenesis and pathophysiology of NAFLD in Hispanics

项目摘要 非酒精性脂肪性肝病（NAFLD/NASH）是美国最常见的肝脏病理， 在西班牙裔的发病率高于非西班牙裔白人的种族/民族中，使这种疾病成为 最大的健康差距。在初步数据中，我们使用NHANES证实了这种健康差异 1988 - 1994数据库。在这项提议中，来自三个机构的研究人员，俄亥俄州大学，查尔斯R。提请 该大学和佛罗里达大学正在合作，通过以下方式揭示这种健康差异的病因： 描绘了其流行病学、细胞和分子基础。肥胖的NAFLD和胰岛素受试者 耐药表现出较低的肝CEACAM1水平，这是一种通过促进肝细胞增殖来限制肝脂肪变性的蛋白质。 胰岛素清除，随后，防止高胰岛素血症驱动的脂肪生成，并通过介导 胰岛素急性释放对肝脏脂肪酸合成酶活性的负面影响。减少CEACAM1 表达是由脂解衍生的脂肪酸激活PPAR α介导的。在初步RNASeq数据中， 分析，我们表明，CEACAM1的mRNA水平显着低于在西班牙人的肝脏比非- 西班牙裔白色肝脏供体，与PNPLA 3脂肪酶表达较低平行，PNPLA 3脂肪酶具有充分记录的 NAFLD/NASH患者和西班牙裔人中的突变。我们还显示了较低水平的CIDEC/FSP27，一种蛋白质， 在腹部脂肪组织（AT）中，与脂肪甘油三酯脂肪酶相互作用，以防止脂肪菌的脂解作用 西班牙裔和非西班牙裔白人接受减肥手术的比例鉴于CIDEC/FSP27在 肥胖受试者的腹部AT，并且因为其突变与人类中增加的脂解相关， 我们假设西班牙裔人与非西班牙裔人相比表现出更高的肝脏新生脂肪生成和脂肪变性， 西班牙裔白人，这是由肝脏CEACAM1表达减少介导的， 脂肪分解过程中的游离脂肪酸通量，这反过来又是由腹部脂肪中CIDEC水平降低引起的 组织.为了验证这一假设，我们将在目标1中使用NHANES数据库来确定流行病学 这种健康差距的根源。在目的2中，我们将描述CIDEC在肝AT中的丢失在肝AT中的作用。 西班牙裔的脂肪变性在目标3中，我们将研究AT中CIDEC的丢失是否会导致AT中CIDEC的减少。 西班牙裔人肝CEACAM1与肝脂肪变性平行。我们的方法旨在研究 在NAFLD差异中起关键作用的组织-肝脏串扰。这项建议的一个优点是跨学科的 Ali Zarrinpar博士（肝移植和肝胆外科医生），Sonia M. Najjar（脂肪肝 疾病和脂质代谢），Vishwajeet Puri（脂肪生物学和脂质代谢）和西奥多弗里德曼 （肝脂肪变性和代谢疾病中的健康差异）。从强劲的初步数据中可以清楚地看出，这些 科学家们在一项提案上进行了富有成效的合作，该提案将描述疾病发病机制中的新途径。 NAFLD在西班牙裔美国人和导致成功的治疗，以减少这种显着的健康差距。

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.