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.

Public Health Relevance

Dr. Henry Ginsberg is applying for an NHLBI Outstanding Investigator Award based on both 40 years of outstanding productivity across preclinical and clinical investigations of the regulation of lipoprotein metabolism and his innovative and far-reaching plans for the next 7 years. These include integrated studies of the pathophysiology of dyslipidemia and non-alcoholic fatty liver disease and are based on studies in cells, mice, and humans. The human studies of lipoprotein kinetics will used single gene defects to allow for discrete phenotyping and will also combine in vivo with iPSC-derived hepatocyte studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
5R35HL135833-05
Application #
10070641
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Fleg, Jerome L
Project Start
2017-01-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Lee, Samuel X; Heine, Markus; Schlein, Christian et al. (2018) FoxO transcription factors are required for hepatic HDL cholesterol clearance. J Clin Invest 128:1615-1626
Nandakumar, Renu; Matveyenko, Anastasiya; Thomas, Tiffany et al. (2018) Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects. J Lipid Res 59:2397-2402
Tsimikas, Sotirios; Fazio, Sergio; Ferdinand, Keith C et al. (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol 71:177-192
Kim, KyeongJin; Goldberg, Ira J; Graham, Mark J et al. (2018) ?-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor. Cell Metab 27:816-827.e4
Ji, HaYeun; Kim, Hye Sung; Kim, Hae-Won et al. (2017) Application of induced pluripotent stem cells to model smooth muscle cell function in vascular diseases. Curr Opin Biomed Eng 1:38-44
Reyes-Soffer, Gissette; Ginsberg, Henry N; Ramakrishnan, Rajasekhar (2017) The metabolism of lipoprotein (a): an ever-evolving story. J Lipid Res 58:1756-1764