# Roles of lysophosphatidic acid in alcoholic liver disease

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $195,938

## Abstract

7. Project Summary/Abstract
Heavy alcohol drinking results in liver steatohepatitis and fibrosis, and ultimately leads to cirrhosis. Liver cirrhosis
is the 12th leading cause of death in the United States and alcohol abuse accounts for around 50% of cirrhosis
cases. Currently, there is no curative pharmacologic treatment for alcoholic steatohepatitis and fibrosis. Thus,
finding therapeutic targets in the progression from steatosis to steatohepatitis and fibrosis would lead to a
reduction in the number of patients with cirrhosis, as well as lower medical costs. This exploratory proposal stems
from our unexpected findings on lysophosphatidic acid (LPA) in alcoholic steatosis and fibrosis. Extracellular LPA
is present in serum at low concentrations as an albumin-bound form and elicits its biological effects via LPA
receptors. We found that antagonism of LPA receptor 1 (LPAR1) reduces de novo lipogenesis in alcoholic
steatosis in mice. Our preliminary data suggest that LPA induces the expression of mature sterol regulatory
element binding transcription factor 1 (SREBP1), a main driver for de novo lipogenesis, in hepatocytes via
atypical protein kinase C (PKCλ/ζ). Furthermore, we found that antagonism of LPAR1 suppresses the activation
of hepatic stellate cells, which are major source of myofibroblasts in liver fibrosis. Mechanistically, LPA/LPAR1
signaling stimulates the nuclear localization of WW domain-containing transcription regulator protein 1 (TAZ), a
downstream effector of the Hippo signaling, and induces the expression of α-smooth muscle actin in activation of
hepatic stellate cells. Based on our preliminary data, we hypothesize that LPA/LPAR1 pathway mediates de novo
lipogenesis in hepatocytes via PKCλ/ζ and SREBP1 in alcohol-induced steatosis. Furthermore, LPA/LPAR1
signaling also induces the activation of hepatic stellate cells via TAZ in liver fibrosis. In Aim 1, we will examine
roles of LPA/LPAR1 in alcoholic steatohepatitis using a new Lpar1-flox mice we have generated. In Aim 2, we will
determine if LPAR1 signaling is required to induce the activation of hepatic stellate cells in alcoholic liver fibrosis
via TAZ. Our preliminary data suggest that LPA/LPAR1 signaling is a new therapeutic target for suppression of
alcoholic steatosis and fibrosis. The outcome of this proposal will be applicable to new drug therapies for
suppression of alcoholic liver disease by targeting LPA/LPAR1 signaling.

## Key facts

- **NIH application ID:** 9847929
- **Project number:** 5R21AA027222-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Kinji Asahina
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,938
- **Award type:** 5
- **Project period:** 2019-01-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847929

## Citation

> US National Institutes of Health, RePORTER application 9847929, Roles of lysophosphatidic acid in alcoholic liver disease (5R21AA027222-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9847929. Licensed CC0.

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