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

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $953,882

## Abstract

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.

## Key facts

- **NIH application ID:** 9841968
- **Project number:** 5R35HL135833-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** HENRY N GINSBERG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $953,882
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841968

## Citation

> US National Institutes of Health, RePORTER application 9841968, Phenotyping Genetic Disorders of Hepatic Lipid and Lipoprotein Metabolism in Cells, Mice, and Men (5R35HL135833-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841968. Licensed CC0.

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