Phenotyping Genetic Disorders of Hepatic Lipid and Lipoprotein Metabolism in Cells, Mice, and Men

总结： 以致动脉粥样硬化性血脂异常为特征的心脏代谢疾病的患病率（血浆 甘油三酯（TG）水平（高甘油三酯血症）、低水平高密度脂蛋白（HDL）胆固醇（C），以及 小胆固醇酯耗尽-TG富集的低密度脂蛋白（LDL））、胰岛素抵抗（IR）和2型 糖尿病（T2 DM）和非酒精性脂肪肝（NAFLD）或其下游并发症，非酒精性脂肪肝（NAFLD） 酒精性脂肪性肝炎（NASH）在过去25年中有所增加。Ginsberg博士领导了一个NHLBI 资助实验室超过40年，从体内研究进展的血浆调节 脂蛋白水平在人类，包括IR的作用，以研究的组装和分泌非常低， 密度脂蛋白（VLDL）在培养的肝细胞，以非酒精性脂肪肝的小鼠模型，包括一些与IR。 金斯伯格和他的合作者处于独特的地位，进行全面综合的研究， 在培养细胞的遗传、分子和全身水平上的血脂异常和NAFLD的病理生理学， 老鼠和人类。拟议的计划是三方的，每个主要领域都有明确的合并机会 调查。它们包括：VLDL组装和分泌的调节， 分泌物在过去的25年里，金斯伯格实验室进行了大量的工作，证明了 apoB的新生物学，并提供了识别调节apoB分泌的潜在靶点所需的见解。 致动脉粥样硬化的脂蛋白。基于最近令人兴奋的数据，我们将集中在肝癌的实验 细胞的方法，以最大限度地分泌备用apoB和/或加载TG到apoB靶向 分泌物维持肝脏脂质稳态的机制。我们计划一系列 确定（a）脂质诱导的ER应激的机制和（B）信号传导途径的实验 内质网应激和内质网自噬之间的联系影响血浆的人类突变的详细表型分析 脂蛋白代谢，对肝脂质稳态有或无影响。本报告中提出的研究 部分将结合联合收割机一个领域，在该领域金斯伯格博士一直是几十年的领导者，示踪动力学 脂蛋白代谢的研究，一个全新的领域金斯伯格实验室，iPSC衍生 肝细胞我们未来工作的这一部分将与最近抵达的一个国家合作开展， 哥伦比亚大学生物医学工程学教授兼 美国国家工程院，再生医学和生物材料领域的领导者。我们将 研究与NAFLD和低脂血症相关的单基因缺陷个体;低脂血症 不伴NAFLD，伴NAFLD的血脂异常。没有一个实验室在同一个人身上定义了 影响血脂和脂蛋白代谢的基因突变的病理生理效应， 肝细胞和整个身体的水平。

Summary: The prevalence of cardiometabolic disorders characterized by an atherogenic dyslipidemia (increased plasma triglyceride (TG) levels (hypertriglyceridemia), low levels of high density lipoprotein (HDL) cholesterol (C), and small cholesteryl ester depleted-TG enriched low density lipoproteins (LDL)), insulin resistance (IR) and type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) or its downstream complication, non- alcoholic steatohepatitis (NASH), have increased over the past 25 years. Dr. Ginsberg, has led an NHLBI- funded laboratory for more than 40 years, progressing from in vivo studies on the regulation of plasma lipoprotein levels in humans, including the role of IR, to studies of the assembly and secretion of very low density lipoproteins (VLDL) in cultured liver cells, to mouse models of NAFLD, including some with IR. Dr. Ginsberg and his collaborators are uniquely positioned to conduct fully integrated studies of the pathophysiology of dyslipidemia and NAFLD at the genetic, molecular, and whole body levels in cultured cells, mice, and humans. The proposed program is tripartite, with clear opportunities for merging of each major area of investigation. They include: Regulation of the assembly and secretion of VLDL assembly and secretion. During the past 25 years, the Ginsberg laboratory produced a body of work demonstrating the novel biology of apoB and provided insights needed to identify potential targets for modulating the secretion of atherogenic lipoproteins from the liver. Based on recent exciting data, we will focus experiments in hepatoma cells on ways to maximize the secretion of spare apoB and or the loading of TG onto apoB targeted to secretion. Mechanisms for the maintenance of hepatic lipid homeostasis. We plan a series of experiments to determine (a) the mechanism for lipid induced ER stress and (b) the signaling pathway between ER stress and ER autophagy. Detailed phenotyping of human mutations affecting plasma lipoprotein metabolism with or without effects on hepatic lipid homeostasis. The studies proposed in this section will combine an area in which Dr. Ginsberg has been a leader for several decades, tracer kinetic studies of lipoprotein metabolism, with an area completely new to the Ginsberg laboratory, iPSC-derived hepatocytes. This component of our future work will be carried out in collaboration with a recent arrival at Columbia, Dr. Kam Leong, Samuel Y Sheng Professor of Biomedical Engineering and a member of the National Academy of Engineering, a leader in the field of regenerative medicine and biomaterials. We will study individuals with single gene defects the are associated with NAFLD and hypolipidemia; hypolipidemia without NAFLD, dyslipidemia with NAFLD. No laboratory has, in the same individual, defined the pathophysiologic effects of mutations in genes affecting lipid and lipoprotein metabolism at both the level of the hepatocyte and the whole body.