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.

项目总结/摘要 在这个应用程序中的主要步骤是了解的机制和途径， 肝VLDL分泌受损促进纤维化和HCC。我们的建议很重要，因为 未满足的需求，需要更细致的方法来确定NAFLD的子集，其中更有针对性的方法可能 为预防和逆转NASH/纤维化和HCC提供信息策略。本提案的背景 是损害肝脏VLDL分泌的遗传缺陷（APOB、APOC 3、MTTP、TM 6SF 2）导致肝脏VLDL分泌减少， 脂肪变性和进展为NASH伴纤维化和HCC，甚至没有肥胖或胰岛素抵抗。此外，本发明还提供了一种方法， VLDL分泌在胰岛素抵抗的NAFLD患者亚组中相对受损（即矛盾地）。 因此，我们的总体科学前提是阐明肝损害的途径， VLDL分泌促进纤维化，HCC将确定用于纤维化逆转的新的可药物化途径， NAFLD/NASH代谢亚组中的HCC预防。我们的建议得到了关键初步意见的支持。 数据包括：（目的1）CDK 4活化作为肝VLDL受损的纤维化损伤的介导因子 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，并将研究相关的潜在机制。(AIM 2）。 我们已经开发了新的组织特异性Tm 6sf 2基因敲除小鼠，以检查代谢和纤维化。 与功能丧失和条件性（WT和E167 K）拯救相关的通路，以辨别 肝脏特异性Tm 6sf 2导致VLDL分泌受损的纤维化和肿瘤发生机制 与Mttp缺失的小鼠相比。该提案的目标是：目标1。什么途径和 介质促进肝纤维化和肝细胞癌伴VLDL分泌受损，这些途径是如何发生的 通过改变脂滴（LD）周转来改变？目的1建立在CDK 4活化途径的发现基础上 并将确定纤维化的脂质介质，以及检查修改LD周转的策略 以减轻纤维化和HCC的发展。AIM 2.肝脏特异性Tm 6sf 2（Tm 6-LKO）缺失， 和拯救，改变肝脏脂质稳态，以及这些适应如何影响肝纤维化损伤 HCC？目的2探讨Tm 6-LKO中LD的形成、周转和FA对VLDL分泌的利用如何改变 以及对肝纤维化和肝细胞癌的影响。我们还想知道这些途径与那些 阐明了Mttp缺失，并进一步阐明了野生型（E167）或突变型（E167） （K167）Tm 6sf 2改变了这些代谢表型，对肝纤维化和HCC有什么影响？ Tm 6 LKO小鼠。总之，我们通过探索新的途径， 纤维化损伤和HCC，重点关注VLDL分泌缺陷作为与亚组直接相关的联系点 NAFLD/NASH的遗传和获得性病因。