# Impaired phospholipid methylation results in decreased lipid droplet lipolysis: Role in hepatic steatosis

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $314,573

## Abstract

PROJECT SUMMARY/ABSTRACT
The development of fatty liver (steatosis) is an early manifestation of alcoholic liver disease (ALD) that can
progress to alcoholic hepatitis and cirrhosis with continued alcohol misuse. Hepatic steatosis is a reversible
early stage of ALD and is, therefore, a prime target for therapeutic intervention. Our long term objectives are to
(i) understand the mechanisms of alcoholic steatosis development and (ii) formulate strategies for
treatment/prevention of this and other fatty liver diseases with similar histopathology and progression history.
We have previously shown that reduction in phosphatidylethanolamine methyltransferase (PEMT) impairs
very-low-density lipoproteins (VLDL) secretion contributing to alcoholic steatosis. PEMT catalyzes the
methylation of phosphatidylethanolamine (PE) to generate phosphatidylcholine (PC), which is necessary for
normal VLDL assembly and secretion. We have further shown that treatment with betaine, a methyl donor,
normalizes PEMT-catalyzed PC synthesis to promote VLDL secretion and prevent alcoholic steatosis.
It has been demonstrated that hepatic cytoplasmic lipid droplets (LDs) play an integral role in VLDL
biogenesis. This is because VLDL assembly is regulated by the availability of triglycerides stored in these LDs
which have to be hydrolyzed to provide substrates for VLDL assembly. LDs are surrounded by a monolayer of
phospholipids; PC is the most abundant class followed by PE and others. Further, an orbit of proteins
determines the metabolic fate of LD lipid stores.
Based on these considerations, we present a novel hypothesis that impaired phospholipid methylation
contributes to the development of hepatic steatosis by impairing LD lipolysis. We propose that the ethanol-
induced impairment in PEMT-catalyzed PC decreases the PC:PE ratio in the LD monolayer. This promotes
generation of enlarged LDs with significant alterations in the complement of LD-associated proteins. These
changes together affect the lipolysis of the LD triglyceride stores disrupting the assembly and secretion of
VLDL resulting in liver steatosis. We further hypothesize that dietary betaine supplementation reverses
alcoholic steatosis by normalizing LD PC:PE ratio and VLDL biogenesis.
To test our hypothesis, we propose the following Specific Aims:
Specific Aim 1: To characterize how ethanol alters the phospholipid and protein composition of hepatic LDs.
Specific Aim 2: To examine the effect of alcohol on LD lipolysis for mobilization of triglyceride stores for
 VLDL secretion.
Specific Aim 3: To determine the effects of betaine on alcohol-induced alterations in LD dynamics.
Completion of these studies will provide insight into the importance of maintaining the essential methylation
reaction catalyzed by PEMT in regulating the dynamics of lipid droplet and preventing the development of
alcoholic steatosis and other chronic liver diseases including non-alcoholic liver disease.

## Key facts

- **NIH application ID:** 9900698
- **Project number:** 5R01AA026723-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Kusum K. Kharbanda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $314,573
- **Award type:** 5
- **Project period:** 2018-05-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900698

## Citation

> US National Institutes of Health, RePORTER application 9900698, Impaired phospholipid methylation results in decreased lipid droplet lipolysis: Role in hepatic steatosis (5R01AA026723-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9900698. Licensed CC0.

---

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