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

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

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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.

项目摘要非酒精性脂肪肝疾病（NAFLD/NASH）是美国最常见的肝病病理在西班牙裔率高于非西班牙裔白人的种族/民族中，这种疾病是其中之一最深刻的健康差异。在初步数据中，我们使用NHANES确认了这种健康差异 1988 - 1994年数据库。在来自俄亥俄州大学三个机构的提案调查员查尔斯·R·德鲁（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。 NAFLD和胰岛素的肥胖受试者抗性表现出较低水平的肝CACAM1，这种蛋白质通过促进肝而限制肝脂肪变性胰岛素清除，随后，防止高胰岛素驱动的脂肪形成，并通过介导急性释放胰岛素对肝脏中脂肪酸合酶活性的负面影响。减少CeCAM1 表达是由脂解衍生的PPARα激活的脂肪分解脂肪酸激活。在初步RNASEQ数据中分析，我们表明，西班牙裔肝脏中CEACAM1的mRNA水平明显低于非非 - 西班牙裔白肝脏供体，与PNPLA3脂肪酶的较低表达并行，该脂肪酶有一个有据可查的文献 NAFLD/NASH患者和西班牙裔的突变。我们还显示较低水平的CIDEC/FSP27，一种蛋白质与脂肪甘油三酸酯脂肪酶相互作用，以防止脂肪脂脂脂解，在腹部脂肪组织中（AT）西班牙裔与非西班牙裔白人正在接受减肥手术。鉴于CIDEC/FSP27在肥胖受试者的腹部，并且由于其突变与人类脂解的增加有关我们假设与非 - 西班牙裔白人，这是由肝CACAM1表达降低来介导的，这是由于过量而导致的脂解过程中的游离脂肪酸通量，这反过组织。 To test this hypothesis, we will in Aim 1, use NHANES databases to identify the epidemiological 这种健康差异的基础。在AIM 2中，我们将描述CIDEC损失的作用西班牙裔中的脂肪变性。在AIM 3中，我们将调查CIDEC损失AT是否导致减少西班牙裔与肝脂肪变性并行的肝CACAM1。我们的方法旨在研究脂肪在NAFLD差异中起关键作用的组织肝串扰。该提议的优势是跨学科 Drs之间的合作。阿里·扎林（Ali Zarrinpar）（肝移植和肝胆管外科医生），索尼亚·纳吉尔（Fatty Liver）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（Theodore Friedman）（代谢性疾病中的肝脂肪变性和健康差异）。从强大的初步数据中可以明显看出科学家已经在一项提案中合作，该提案将描绘出新的途径的发病机理 NAFLD在西班牙裔中，导致成功治疗以减少这种显着的健康差异。