Impaired VLDL secretion, progression and reversal of hepatic fibrogenesis

VLDL 分泌受损、肝纤维化进展和逆转

• 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
• 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

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.

项目摘要/摘要 本应用程序中的主要目标是了解 肝VLDL分泌受损可促进纤维化和HCC。我们的建议很重要，因为 未满足的方法更细微的方法来识别NAFLD的子集，而更量化的方法可能 告知纳什/纤维化和HCC的预防和逆转策略。该提议的背景 是遗传缺陷（APOB，APOB3，MTTP，TM6SF2）会损害肝VLDL分泌 即使没有肥胖或胰岛素抵抗，脂肪变性并以纤维化和HCC为nash。此外， VLDL的分泌相对（矛盾地）在抗胰岛素耐药性NAFLD患者的一部分中受到了损害。 因此，我们的整体科学前提是阐明肝脏受损的途径 VLDL的分泌促进纤维化，HCC将确定新颖的，可毒品的纤维化途径 NAFLD/NASH代谢子集中的HCC预防。我们的建议得到关键初步的支持 数据包括：（ AIM 1）CDK4激活作为纤维化损伤的介质，肝VLDL受损 肝特异性微粒体甘油三酸酯转移蛋白（MTTP）缺失（MTTP-LKO）后分泌。我们也是 在MTTP-LKO小鼠中找到增加的遗传毒性HCC，并将追求涉及的潜在机制。 （目标2）。 我们已经开发了新型组织特异性TM6SF2基因敲除小鼠，以检查代谢和纤维化 与功能和条件丧失（WT和E167K）救援相关的途径，以辨别 纤维化和肿瘤发生的机制，肝脏特异性TM6SF2产生的VLDL分泌受损 与具有MTTP缺失的小鼠相比，删除。该提议的目的是：目标1。 介质以肝VLDL分泌受损而促进纤维化和HCC，这些途径如何 通过更改脂质液滴（LD）周转率修改？ AIM 1以CDK4激活途径为基础 并将确定纤维发生的脂肪组介质，并检查修改LD更新的策略 减轻纤维化和HCC的发展。目标2。肝脏特异性TM6SF2（TM6-LKO）删除如何 和救援，改变肝脂质稳态，这些适应如何影响肝纤维造成损伤 和HCC？ AIM 2询问LD形成，营业额和FA利用率如何在TM6-LKO中改变 小鼠以及对纤维化和HCC的影响。我们还问这些途径与这些途径有何不同 用MTTP缺失阐明，此外，AAV8介导的野生型（E167）或突变体的救援 （K167）TM6SF2修改了这些代谢表型，并对肝纤维发生和HCC的影响 TM6 LKO小鼠。综上 纤维造成损伤和HCC，专注于有缺陷的VLDL分泌作为与子集直接相关的Nexus点 NAFLD/NASH的遗传和获得的病因。