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: 10396531
• 负责人: Nicholas O. Davidson
• 金额: $ 52.22万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396531
• 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; 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; insight; kindred; lipid biosynthesis; lipid mediator; lipidomics; 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 本应用程序的主要目标是了解 肝脏极低密度脂蛋白分泌受损会促进纤维化和肝细胞癌。我们的建议意义重大，因为 对确定NAFLD子集的更细微方法的需求尚未得到满足，在这些子集中，更定制的方法可能 告知预防和逆转NASH/纤维化和肝细胞癌的策略。这项提议的背景 损害肝脏VLDL分泌的遗传缺陷(APOB、APOC3、MTTP、TM6SF2)是否会导致肝脏 脂肪变性和进展为NASH伴纤维化和肝细胞癌，即使没有肥胖或胰岛素抵抗。此外, 在胰岛素抵抗的NAFLD患者中，极低密度脂蛋白的分泌相对(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 极低密度脂蛋白的分泌促进纤维化，肝细胞癌将确定新的，可用来逆转和治疗纤维化的药物途径 非酒精性脂肪肝/非酒精性脂肪肝的代谢子组中的肝癌预防。我们的建议得到了关键的初步支持 数据包括：(目标1)CDK4活化作为肝VLDL受损的纤维化损伤的介质 肝微粒体甘油三酯转移蛋白(MTTP)缺失后分泌(MTTP-LKO)。我们也 在MTTP-LKO小鼠中发现基因毒性增加的肝癌，并将探讨相关的潜在机制。(目标2)。 我们开发了新的组织特异性TM6SF2基因敲除小鼠来检测代谢和纤维化 与功能丧失和条件性(WT和E167K)救援相关的途径，以识别 肝脏特异性TM6SF2导致极低密度脂蛋白分泌受损的纤维化和肿瘤发生机制 缺失，与MTTP缺失的小鼠相比。这项建议的目的是：目标1.什么途径和 介质促进纤维化和肝细胞癌并伴有肝脏VLDL分泌受损，这些途径是如何实现的 被改变的脂滴(LD)周转所修饰？AIM 1建立在CDK4激活通路研究结果的基础上 并将确定肝纤维化的脂类介质以及研究改变LD周转的策略 减轻肝纤维化和肝细胞癌的发展。目的2.肝脏特异性TM6SF2(Tm6-LKO)缺失是如何发生的， 以及挽救、改变肝脏脂质稳态以及这些适应如何影响肝纤维化损伤 那肝癌呢？目的2研究Tm6-LKO中LD的形成、周转和对VLDL分泌的FA利用是如何改变的 以及对肝纤维化和肝细胞癌的影响。我们还问，这些路径与那些路径有什么不同 阐明了MTTP缺失，以及AAV8如何介导对野生型(E167)或突变体的营救 (K167)TM6SF2改变这些代谢表型及其对肝纤维化和肝细胞癌的影响 TM6LKO小鼠。总之，我们通过探索新的途径来解决关键的知识差距 纤维性损伤和肝细胞癌，集中在VLDL分泌缺陷作为与亚组直接相关的连接点 NAFLD/NASH的遗传和获得性病因。

项目成果

SARS-CoV-2 Infection Dysregulates the Metabolomic and Lipidomic Profiles of Serum.

• DOI: 10.1016/j.isci.2020.101645
• 发表时间: 2020-10-23
• 期刊: iScience
• 影响因子: 5.8
• 作者: Bruzzone C;Bizkarguenaga M;Gil-Redondo R;Diercks T;Arana E;García de Vicuña A;Seco M;Bosch A;Palazón A;San Juan I;Laín A;Gil-Martínez J;Bernardo-Seisdedos G;Fernández-Ramos D;Lopitz-Otsoa F;Embade N;Lu S;Mato JM;Millet O
• 通讯作者: Millet O