# Mechanisms regulating lipoprotein secretion and lipid metabolism

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $379,830

## Abstract

Project Summary/Abstract
Disruption of lipid metabolism has been associated with metabolic syndrome including obesity,
diabetes and nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by the accumulation of
lipids in hepatocytes that can progress to nonalcoholic steatohepatitis (NASH), which has increased
hepatocyte death, inflammation and fibrosis. The molecular basis of the development and progression of
NAFLD/NASH are still poorly understood. As a result, no effective therapeutic treatments for this burgeoning
health problem are available. Thus, there is a clear unmet research need in this area. Hepatic very-low-density
lipoprotein (VLDL) secretion is essential in regulating intrahepatic and intravascular lipid homeostasis. Impaired
VLDL secretion leads to hepatic steatosis and hypolipidemia. Vacuole membrane protein 1 (VMP1) is an ER
membrane protein that regulates autophagy by promoting the closure of autophagosomes. Recent evidence
demonstrates that VMP1 plays a critical role in lipoprotein secretion independent of its autophagy function in
cultured hepatoma cells and zebrafish. VMP1 is also an ER scramblase to regulate cholesterol homeostasis.
The major OBJECTIVES of this application are to understand the role and mechanisms by which VMP1
regulates lipid metabolism and NAFLD progression. Our proposal is SIGNIFICANT because it is to investigate
a novel pathway in regulating lipid metabolism and development of NAFLD. Work performed under this
application will enrich the NAFLD field regarding the critical role of VMP1 as a central regulator of ER-
mitochondria crosstalk, which regulate VLDL secretion at multilayers in the development of NAFLD. Our
SICENTIFIC PREMISE is that loss of VMP1 impairs VLDL secretion and promotes NAFLD/NASH. Our
proposal is supported by KEY PRELIMINARY DATA including: 1) Hepatocyte-specific deletion of VMP1 in
mice impaired VLDL secretion resulting in hepatic steatosis and NASH; and 2) VMP1 is critical to concert ER-
mitochondria crosstalk to regulate VLDL secretion in NAFLD. Three SPECIFIC AIMS are proposed: 1)
Determine the mechanisms by which loss of VMP1 decreases hepatic phosphatidylcholine and
phosphatidylethanolamine content resulting in impaired VLDL secretion and NASH; 2) Decipher the role and
the domains of VMP1 in regulating VLDL secretion, phospholipid synthesis and autophagy; and 3) Determine
the mechanisms by which VMP1 ameliorates diet-induced impaired VLDL secretion and NASH. The LONG-
TERM GOAL of this work is to identify VMP1-dependent pathways in regulating lipid metabolism and the
pathogenesis of NAFLD/NASH, which may lead to develop potential strategies for treating NASH and other
metabolic diseases by targeting VMP1.

## Key facts

- **NIH application ID:** 10758850
- **Project number:** 5R01DK134737-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Hongmin Ni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,830
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758850

## Citation

> US National Institutes of Health, RePORTER application 10758850, Mechanisms regulating lipoprotein secretion and lipid metabolism (5R01DK134737-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10758850. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*