miR-378/378* promotes hepatic lipid accumulation and progression of NAFLD to NASH

miR-378/378*促进肝脏脂质积累以及NAFLD向NASH的进展

• 批准号: 9336294
• 负责人: Guisheng Song
• 金额: $ 41.36万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336294
• 关键词: Address; Affect; Antisense Oligonucleotide Therapy; Binding; Bioinformatics; Cardiovascular Diseases; Cells; Cirrhosis; Data; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Experimental Designs; FDA approved; Fatty Liver; Fibrosis; Gatekeeping; Gene Targeting; General Population; Genes; Goals; Hepatic; Hepatitis C; Hepatocyte; High Fat Diet; Human; Hyperlipidemia; Individual; Industrialization; Injectable; Lipids; Liver; Liver diseases; Mediating; Metabolic Diseases; Metabolic syndrome; MicroRNAs; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Physiological; Plasma; Play; Prealbumin; Prevalence; Primary carcinoma of the liver cells; Process; Regulation; Research; Risk; Risk Factors; Role; Sampling; Serum; Site; Steatohepatitis; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcription Repressor/Corepressor; Triglycerides; Untranslated RNA; base; cell type; design; gain of function; in vivo; inhibitor/antagonist; insight; interest; knock-down; lipid metabolism; liver biopsy; liver injury; mouse model; new therapeutic target; non-alcoholic; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; nuclear respiratory factor; overexpression; prevent; promoter; public health relevance; sortilin; tool; treatment response; validation studies; Address; Affect; Antisense Oligonucleotide Therapy; Binding; Bioinformatics; Cardiovascular Diseases; Cells; Cirrhosis; Data; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Experimental Designs; FDA approved; Fatty Liver; Fibrosis; Gatekeeping; Gene Targeting; General Population; Genes; Goals; Hepatic; Hepatitis C; Hepatocyte; High Fat Diet; Human; Hyperlipidemia; Individual; Industrialization; Injectable; Lipids; Liver; Liver diseases; Mediating; Metabolic Diseases; Metabolic syndrome; MicroRNAs; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Physiological; Plasma; Play; Prealbumin; Prevalence; Primary carcinoma of the liver cells; Process; Regulation; Research; Risk; Risk Factors; Role; Sampling; Serum; Site; Steatohepatitis; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcription Repressor/Corepressor; Triglycerides; Untranslated RNA; base; cell type; design; gain of function; in vivo; inhibitor/antagonist; insight; interest; knock-down; lipid metabolism; liver biopsy; liver injury; mouse model; new therapeutic target; non-alcoholic; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; nuclear respiratory factor; overexpression; prevent; promoter; public health relevance; sortilin; tool; treatment response; validation studies

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with a prevalence estimated to be in 20-30% of the general population within the industrialized world. It is associated with a number of risk factors, including, type II diabetes, hepatocellular carcinoma (HCC), cardiovascular disease, and hyperlipidemia. MicroRNAs (miRNAs) are a new class of naturally occurring small non-coding RNAs that are known to play critical roles in a number of metabolic disorders, in part, by inhibiting expression of target genes. It is now well established that the introduction of specific miRNAs, or antimiRs into diseased cells and tissues can induce favorable therapeutic responses. Indeed, miR-122 inhibitor has entered phase III clinical trials as a therapeutic agent for HCV infection. Hepatocytes are the major cell type that controls lipid metabolism and the primary site of lipid accumulation in NAFLD. To address their potential role in the development of NAFLD, we initially identified miRNAs that are highly and specifically expressed in hepatocytes and found that one of them, miR-378/378*, is significantly induced in the livers of mice maintained on a high fat diet (HFD). Further, by inhibiting miR-378/378* we were able to significantly prevent hepatic lipid accumulation and hyperlipidemia in HFD-treated mice. Bioinformatic and validation studies revealed that miR-378/378* directly inhibited NRF1 (nuclear respiratory factor 1) and SORT1 (Sortilin 1), two gatekeepers of NASH and dyslipidemia, and induced expression of TNFα, a promoter of NASH. These findings led us to hypothesize that miR-378/378* promotes hepatic lipid accumulation and the progression of NAFLD to NASH by simultaneously modulating expression of NRF1, SORT1 and TNFα. The objective of this project is to determine the roles of the crosstalk of miR-378/378* with NRF, SORT1 and TNFα in regulating hepatic lipid accumulation and the progression of NAFLD to NASH. The long-term goal of this study is to elucidate the underlying mechanism(s) of NAFLD and its progression to NASH, and develop miRNA inhibitors as therapeutic agents for both disorders. Three Specific Aims are designed to test our hypothesis. Specifically, we will (1) establish gain-of-function studies for miR-378/378* in affecting hepatic lipids in HFD-treated mice, and determine whether their inhibition prevents hepatic lipid accumulation via modulation of NRF1 and SORT1; (2) determine the role of miR-378/378* in promoting progression of NAFLD to NASH, and elucidate the underlying mechanisms of this process; and (3) evaluate the levels of miR-378/378*, SORT1, NRF1 and TNFα in a set of liver samples from patients with a spectrum of NAFLD and NASH. Our studies are designed to establish miR-378/378* as a new pathway for the regulation of hepatic lipid metabolism and the progression of NAFLD to NASH. The combination of strong preliminary data and a logical and rationally based experimental design make this project highly feasible. The results will provide novel insights into the physiological roles and mechanisms of miRNAs, in addition to their potential therapeutic application for both of these hepatic disorders.

描述（由适用提供）：非酒精性脂肪肝病（NAFLD）是最常见的肝病，估计在工业化世界内的普通人群的患病率为20％至30％。它与许多危险因素有关，包括II型糖尿病，肝细胞癌（HCC），心血管疾病和高脂血症。 microRNA（miRNA）是一类新的天然存在的小型非编码RNA，已知在许多代谢性疾病中起着关键作用，部分原因是通过抑制靶基因的表达。现在已经很好地确定，将特定的miRNA或抗杀菌物引入解剖细胞和组织可以诱导有利的治疗反应。实际上，miR-122抑制剂已作为HCV感染的治疗剂进入了III期临床试验。肝细胞是控制脂质代谢和NAFLD中脂质积累的主要位点的主要细胞类型。为了解决它们在NAFLD的发展中的潜在作用，我们最初确定了在肝细胞中高度和专门表达的miRNA，发现其中一个MiR-378/378*是在维持高脂肪饮食（HFD）的小鼠生活中显着诱导的。此外，通过抑制miR-378/378*，我们能够显着防止HFD处理的小鼠中的肝脂质积累和高脂血症。生物信息学和验证研究表明，miR-378/378*直接抑制NRF1（核呼吸因子1）和Sort1（Sortilin 1），NASH和血脂异常的两个守门员，以及诱导的NASH启动子TNFα的表达。这些发现使我们假设miR-378/378*通过简单地放置调节NRF1，Sort1和TNFα的表达来促进肝脂质积累和NAFLD向NASH的发展。该项目的目的是确定miR-378/378*与NRF，Sort1和TNFα的串扰在控制肝脂质积累以及NAFLD向NASH的进展中的作用。这项研究的长期目标是阐明NAFLD的潜在机制及其向NASH的发展，并发展为miRNA抑制剂作为两种疾病的治疗剂。三个特定目标旨在检验我们的假设。具体而言，我们将（1）在影响HFD处理的小鼠中影响miR-378/378*的功能收益研究，并确定它们的抑制是否通过调节NRF1和Sort1的调节来阻止肝脂质积累； （2）确定miR-378/378*在促进NAFLD向NASH的进展中的作用，并阐明该过程的基本机制； （3）在一组NAFLD和NASH患者的一组肝脏样品中评估miR-378/378*，Sort1，NRF1和TNFα的水平。我们的研究旨在建立miR-378/378*作为调节肝脂质代谢的新途径，以及NAFLD向NASH的发展。强大的初步数据和基于逻辑和理性的实验设计的结合使该项目高度可行。除了它们对这两种肝疾病的潜在治疗应用外，结果还将为miRNA的身体作用和机制提供新的见解。