Novel pathways in the pathogenesis and pathophysiology of NAFLD in Hispanics

西班牙裔 NAFLD 发病机制和病理生理学的新途径

基本信息

批准号：
10527339
负责人：
THEODORE C FRIEDMAN
金额：
$ 56.45万
依托单位：
OHIO UNIVERSITY ATHENS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-12 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527339
关键词：
Abdomen Acculturation Acute Adipocytes Adipose tissue Age Biological Models Biology Black Populations Body Composition CEACAM1 Cirrhosis Collaborations Data Data Analyses Databases Diet Disease Disease Resistance Disparity Eating Elasticity Enzymes Epidemiology Ethnic Origin Ethnic Population Etiology Exhibits Fatty Acids Fatty Liver Fatty-acid synthase Female Fibrosis Florida Functional disorder General Population Genetic Polymorphism Health Hepatic Hepatobiliary Hepatocyte High Prevalence Hispanic Hispanic Populations Histologic Human Hyperinsulinism Impairment Incidence Institution Insulin Insulin Resistance Insulin Signaling Pathway Laboratories Lipase Lipolysis Liver Liver diseases Malonyl Coenzyme A Measures Mediating Messenger RNA Metabolic Metabolic Diseases Metabolic syndrome Mitochondria Modeling Molecular Mus Mutation National Health and Nutrition Examination Survey Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Not Hispanic or Latino Obesity Ohio PPAR alpha Palmitic Acids Pathogenesis Pathology Pathway interactions Patients Physical activity Play Population Primary carcinoma of the liver cells Productivity Proteins Quantitative Reverse Transcriptase PCR Race Recovery Research Personnel Role Sample Size Sampling Scientist Smoking Steatohepatitis Surgeon Testing Tissues Transgenic Organisms Universities Visceral Weight Wild Type Mouse Woman abdominal fat adenoviral mediated bariatric surgery demographics design disease disparity effective therapy epidemiology study fatty liver disease gain of function health disparity human tissue improved inflammatory marker interdisciplinary collaboration lipid biosynthesis lipid metabolism liver function liver transplantation loss of function male non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics obese person overexpression oxidation prevent racial disparity recruit simple steatosis transcriptome sequencing ultrasound

项目摘要

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.

项目概要非酒精性脂肪性肝病 (NAFLD/NASH) 是美国最常见的肝脏疾病，其差异很大在种族/族裔中，西班牙裔的发病率高于非西班牙裔白人，使这种疾病成为最常见的疾病之一最深刻的健康差异。在初步数据中，我们已经使用 NHANES 确认了这种健康差异 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、Charles R. Drew 大学和佛罗里达大学正在合作揭示这种健康差异的病因描述其流行病学、细胞和分子基础。患有 NAFLD 和胰岛素的肥胖受试者抵抗力表现出较低水平的肝脏 CEACAM1，这是一种通过促进肝脏功能来限制肝脏脂肪变性的蛋白质胰岛素清除率，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酶活性的负面影响。 CEACAM1 的减少表达是由脂解衍生的脂肪酸激活 PPAR α 介导的。在初步 RNASeq 数据中分析表明，西班牙裔美国人肝脏中 CEACAM1 的 mRNA 水平显着低于非西班牙裔美国人。西班牙裔白人肝脏供体，同时 PNPLA3 脂肪酶表达较低，该酶具有有据可查的 NAFLD/NASH 患者和西班牙裔的突变。我们还发现 CIDEC/FSP27 水平较低，这种蛋白质与脂肪甘油三酯脂肪酶相互作用，防止腹部脂肪组织 (AT) 中脂肪细胞的脂肪分解西班牙裔与非西班牙裔白人接受减肥手术的比例。鉴于 CIDEC/FSP27 的减少肥胖受试者的腹部 AT，并且由于其突变与人类脂肪分解增加有关，我们假设，与非西班牙裔美国人相比，西班牙裔美国人表现出更高的肝脏从头脂肪生成和脂肪变性西班牙裔白人，这是由过量的肝脏 CEACAM1 表达减少介导的脂肪分解过程中游离脂肪酸的流动，这又是由腹部脂肪中 CIDEC 水平降低引起的组织。为了检验这一假设，我们将在目标 1 中使用 NHANES 数据库来识别流行病学造成这种健康差异的根源。在目标 2 中，我们将描述 AT 中 CIDEC 缺失在肝脏中的作用西班牙裔人的脂肪变性。在目标 3 中，我们将研究 AT 中 CIDEC 的丢失是否会导致西班牙裔人的肝脏 CEACAM1 与肝脂肪变性平行。我们的方法旨在研究脂肪组织-肝脏串扰在 NAFLD 差异中发挥着关键作用。该提案的优点是跨学科博士之间的合作。 Ali Zarrinpar（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 Theodore Friedman （肝脂肪变性和代谢疾病中的健康差异）。从强有力的初步数据可以清楚地看出，这些科学家们富有成效地合作提出了一项提案，该提案将描述疾病发病机制的新途径西班牙裔非酒精性脂肪肝 (NAFLD) 并导致成功的治疗方法以缩小这种显着的健康差距。