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疾病，差异很大 在西班牙裔美国人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 最严重的健康差距。在初步数据中，我们已经使用NHANES证实了这种健康差距 1988-1994年数据库。在这项提案中，来自三个机构的研究人员，俄亥俄大学，查尔斯·R·德鲁 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距的原因 描述其流行病学、细胞和分子基础。伴有NAFLD和胰岛素的肥胖者 耐药性表现为肝脏CEACAM1水平较低，这是一种通过促进肝脏脂肪变性来限制肝脏脂肪变性的蛋白质 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。CEACAM1的简化 PPARα的表达是由脂解衍生的脂肪酸激活PPARα介导的。在初步的RNAseq数据中 分析表明，西班牙裔肝脏中CEACAM1的mRNA水平显著低于非西班牙裔 西班牙裔白人肝脏捐赠者，与PNPLA3脂肪酶的低表达平行，该脂肪酶含有已有充分记录的 非酒精性脂肪肝/非酒精性脂肪肝患者和拉美裔患者的突变。我们还显示CIDEC/FSP27的水平较低，这是一种 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分解 接受减肥手术的西班牙裔白人和非西班牙裔白人的比例。鉴于CIDEC/FSP27在 肥胖受试者的腹部AT，因为它的突变与人类脂肪分解增加有关， 我们假设，与非拉美裔美国人相比，拉美裔美国人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，这是由过量的肝脏CEACAM1表达减少所介导的 脂解过程中的游离脂肪酸流动，而这又是由腹部脂肪中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 这种健康差距的基础。在目标2中，我们将描述CIDEC缺失在肝脏AT中的作用 西班牙裔的脂肪变性。在目标3中，我们将调查AT失去CIDEC是否导致 西班牙人的肝脏CEACAM1与肝脏脂肪变性平行。我们的方法是为了研究脂肪 组织-肝脏串扰在NAFLD差异中起着关键作用。这项提议的一个优点是跨学科 阿里·扎林帕尔博士(肝脏移植和肝胆外科医生)、索尼娅·M·纳贾尔博士(脂肪肝)之间的合作 疾病和脂类代谢)、Vishwajeet Puri(脂肪生物学和脂类代谢)和Theodore Friedman 《代谢性疾病中的肝脏脂肪变性和健康差异》。从强劲的初步数据中可以清楚地看到，这些 科学家们卓有成效地合作了一项提议，该提议将描绘出糖尿病发病机制中的新途径 非酒精性脂肪性肝病在拉美裔美国人中的发病率，并导致成功的治疗，以缩小这一显着的健康差距。

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.