Impaired VLDL secretion, progression and reversal of hepatic fibrogenesis

VLDL 分泌受损、肝纤维化进展和逆转

基本信息

批准号：
9978062
负责人：
Nicholas O. Davidson
金额：
$ 52.61万
依托单位：
WASHINGTON UNIVERSITY
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：
2019-07-16 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978062
关键词：
Address Atherosclerosis CD36 gene CDK4 gene Cardiovascular system Cholesterol Data Development Diet Diethylnitrosamine Dyslipidemias Etiology Exhibits Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Gap Junctions Genetic Hepatic Hepatic Fibrogenesis Hepatocyte Homeostasis Human Impairment In Vitro Inflammation Injury Insulin Resistance Knockout Mice LDL Cholesterol Lipoproteins Link Lipids Liver Low-Density Lipoproteins Malignant Neoplasms Malignant neoplasm of liver Mediating Mediator of activation protein Metabolic Mus Mutation Obesity Obesity Epidemic Pathway interactions Patients Pharmacology Phenotype Predisposition Prevalence Prevention Prevention strategy Primary carcinoma of the liver cells Publishing Role Serum Signal Transduction Steatohepatitis The Cancer Genome Atlas Therapeutic Tissues Tumor Burden Very low density lipoprotein base cancer prevention cardiovascular risk factor druggable target exome sequencing exosome fibrogenesis gene therapy genotoxicity inhibitor/antagonist insight kindred lipid biosynthesis lipid mediator loss of function macrophage metabolic phenotype microsomal triglyceride transfer protein mortality mouse model mutant non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel patient subsets personalized approach prevent stellate cell tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT The major OBJECTIVES in this application are to understand the mechanisms and pathways by which impaired hepatic VLDL secretion promotes fibrosis and HCC. Our proposal is SIGNIFICANT because of the unmet need for a more nuanced approach to identify subsets of NAFLD where a more tailored approach might inform strategies for prevention and reversal of NASH/fibrosis and HCC. The BACKGROUND to this proposal is that genetic defects (APOB, APOC3, MTTP, TM6SF2) that impair hepatic VLDL secretion cause hepatic steatosis and progress to NASH with fibrosis and HCC, even without obesity or insulin resistance. In addition, VLDL secretion is relatively (ie paradoxically) impaired in a subset of insulin-resistant, NAFLD patients. Accordingly our overall SCIENTIFIC PREMISE is that is that elucidating pathways whereby impaired hepatic VLDL secretion promotes fibrosis and HCC will identify novel, druggable pathways for fibrosis reversal and HCC prevention in a metabolic subset of NAFLD/NASH. Our proposal is supported by KEY PRELIMINARY DATA including: (AIM 1) CDK4 activation as a mediator of fibrogenic injury with impaired hepatic VLDL secretion following liver-specific microsomal triglyceride transfer protein (Mttp) deletion (Mttp-LKO). We also find increased genotoxic HCC in Mttp-LKO mice and will pursue the underlying mechanisms involved. (AIM 2). We have developed novel tissue-specific Tm6sf2 knockout mice to examine the metabolic and fibrogenic pathways associated with both loss of function and conditional (WT and E167K) rescue, to discern mechanisms of fibrosis and tumorigenesis with impaired VLDL secretion resulting from liver-specific Tm6sf2 deletion, compared to mice with Mttp deletion. The AIMS of this proposal are: AIM 1. What pathways and mediators promote fibrosis and HCC with impaired hepatic VLDL secretion and how are these pathways modified by altered lipid droplet (LD) turnover? Aim 1 builds on the findings with CDK4 activation pathways and will identify lipidomic mediators of fibrogenesis as well as examining strategies for modifying LD turnover to mitigate the development of fibrosis and HCC. AIM 2. How does liver specific Tm6sf2 (Tm6-LKO) deletion, and rescue, alter hepatic lipid homeostasis and how do these adaptations influence hepatic fibrogenic injury and HCC? Aim 2 asks how LD formation, turnover and FA utilization for VLDL secretion is altered in Tm6-LKO mice and with what implications for fibrosis and HCC. We also ask how those pathways differ from those elucidated with Mttp deletion and, further, how AAV8-mediated rescue with either wild-type (E167) or mutant (K167) Tm6sf2 modifies those metabolic phenotypes and with what impact for hepatic fibrogenesis and HCC in Tm6 LKO mice. Taken together, we address a CRITICAL KNOWLEDGE GAP by exploring novel pathways of fibrogenic injury and HCC, focusing on defective VLDL secretion as a nexus point directly relevant to a subset of genetic and acquired etiologies of NAFLD/NASH.

项目概要/摘要本应用的主要目标是了解其机制和途径肝脏 VLDL 分泌受损会促进纤维化和肝癌。我们的建议意义重大，因为对更细致的方法来识别 NAFLD 子集的需求未得到满足，而更有针对性的方法可能会为预防和逆转 NASH/纤维化和 HCC 的策略提供信息。本提案的背景是遗传缺陷（APOB、APOC3、MTTP、TM6SF2）损害肝脏 VLDL 分泌，导致肝脏即使没有肥胖或胰岛素抵抗，脂肪变性并进展为伴有纤维化和肝癌的 NASH。此外，在胰岛素抵抗的 NAFLD 患者中，VLDL 分泌相对（即矛盾地）受损。因此，我们的总体科学前提是阐明肝脏受损的途径 VLDL 分泌促进纤维化，HCC 将确定新的、可药物化的途径来逆转纤维化和 NAFLD/NASH 代谢亚型中的 HCC 预防。我们的提案得到了 KEY PRELIMINARY 的支持数据包括：(AIM 1) CDK4 激活作为肝脏 VLDL 受损的纤维形成损伤的介质肝脏特异性微粒体甘油三酯转移蛋白（Mttp）缺失（Mttp-LKO）后的分泌。我们也在 Mttp-LKO 小鼠中发现基因毒性 HCC 增加，并将探究所涉及的潜在机制。（目标 2）。我们开发了新型组织特异性 Tm6sf2 敲除小鼠来检查代谢和纤维形成与功能丧失和有条件（WT 和 E167K）救援相关的途径，以辨别肝脏特异性 Tm6sf2 导致 VLDL 分泌受损导致纤维化和肿瘤发生的机制与 Mttp 缺失的小鼠相比。该提案的目标是：目标 1. 哪些途径和介质促进纤维化和 HCC，同时肝脏 VLDL 分泌受损，这些途径如何通过改变脂滴（LD）周转而改变？目标 1 基于 CDK4 激活途径的发现并将确定纤维形成的脂质组介质以及检查改变 LD 周转的策略减轻纤维化和肝癌的发展。目的 2. 肝脏特异性 Tm6sf2 (Tm6-LKO) 缺失如何发生？和拯救、改变肝脂质稳态以及这些适应如何影响肝纤维化损伤和肝癌？目标 2 询问 Tm6-LKO 中 VLDL 分泌的 LD 形成、周转和 FA 利用是如何改变的小鼠以及对纤维化和肝癌的影响。我们还询问这些途径与其他途径有何不同阐明了 Mttp 缺失，以及 AAV8 如何介导野生型 (E167) 或突变体的拯救 (K167) Tm6sf2 改变这些代谢表型以及对肝纤维化和 HCC 的影响 Tm6 LKO 小鼠。总而言之，我们通过探索新的途径来解决关键知识差距纤维化损伤和 HCC，重点关注 VLDL 分泌缺陷作为与子集直接相关的连接点 NAFLD/NASH 的遗传和获得性病因学。