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

细胞、小鼠和男性肝脏脂质和脂蛋白代谢的表型遗传疾病

• 批准号: 10524759
• 负责人: HENRY N GINSBERG
• 金额: $ 95.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524759
• 关键词: Academy; Affect; Apolipoproteins B; Area; Autophagocytosis; Award; Biocompatible Materials; Biology; Biomedical Engineering; Cardiometabolic Disease; Cells; Cholesterol Esters; Collaborations; Complication; Cultured Cells; Data; Dyslipidemias; Engineering; Functional disorder; Funding; Future; Genes; Genetic; Genetic Diseases; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Homeostasis; Human; Hypertriglyceridemia; Individual; Insulin Resistance; Investigation; Kinetics; Laboratories; Lipids; Lipoproteins; Liver; Liver diseases; Low-Density Lipoproteins; Maintenance; Metabolism; Molecular; Mus; Mutation; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Phenotype; Plasma; Positioning Attribute; Prevalence; Productivity; Regenerative Medicine; Regulation; Research Personnel; Role; Series; Signal Pathway; Single-Gene Defect; Tracer; Triglycerides; Very low density lipoprotein; Work; clinical investigation; endoplasmic reticulum stress; experimental study; hepatoma cell; hypolipidemia; in vivo; induced pluripotent stem cell; innovation; insight; member; men; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pre-clinical; professor; programs

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.

简介:

项目成果

TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk.

• DOI: 10.1096/fj.202101607r
• 发表时间: 2022-03
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Relationship of apolipoprotein(a) isoform size with clearance and production of lipoprotein(a) in a diverse cohort.

• DOI: 10.1016/j.jlr.2023.100336
• 发表时间: 2023-03
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Matveyenko, Anastasiya;Matienzo, Nelsa;Ginsberg, Henry;Nandakumar, Renu;Seid, Heather;Ramakrishnan, Rajasekhar;Holleran, Steve;Thomas, Tiffany;Reyes-Soffer, Gissette
• 通讯作者: Reyes-Soffer, Gissette

Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.

肝脏 SMLR1 的缺失会导致肝脂肪变性，并由于肝脏 VLDL 分泌减少而预防动脉粥样硬化。

• DOI: 10.1002/hep.32709
• 发表时间: 2023-11-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: van Zwol, Willemien;Rimbert, Antoine;Wolters, Justina C.;Smit, Marieke;Bloks, Vincent W.;Kloosterhuis, Niels J.;Huijkman, Nicolette C. A.;Koster, Mirjam H.;Tharehalli, Umesh;de Neck, Simon M.;Bournez, Colin;Fuh, Marceline M.;Kuipers, Jeroen;Rajan, Sujith;de Bruin, Alain;Ginsberg, Henry N.;van Westen, Gerard J. P.;Hussain, M. Mahmood;Scheja, Ludger;Heeren, Joerg;Zimmerman, Philip;van de Sluis, Bart;Kuivenhoven, Jan Albert
• 通讯作者: Kuivenhoven, Jan Albert

Hepatocytes Deficient in Nuclear Envelope Protein Lamina-associated Polypeptide 1 are an Ideal Mammalian System to Study Intranuclear Lipid Droplets.

• DOI: 10.1016/j.jlr.2022.100277
• 发表时间: 2022-10
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Ostlund, Cecilia;Hernandez-Ono, Antonio;Turk, Samantha J.;Dauer, William T.;Ginsberg, Henry N.;Worman, Howard J.;Shin, Ji-Yeon
• 通讯作者: Shin, Ji-Yeon

Application of induced pluripotent stem cells to model smooth muscle cell function in vascular diseases.

• DOI: 10.1016/j.cobme.2017.02.005
• 发表时间: 2017-03
• 期刊: Current opinion in biomedical engineering
• 影响因子: 3.9
• 作者: Ji H;Kim HS;Kim HW;Leong KW
• 通讯作者: Leong KW