# Study the role of oxysterol sulfates in NAFLD development

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

Project Summary
 The liver plays a pivotal role in the maintenance of lipid homeostasis. Accumulation of lipids in the liver with
no alcoholic consumption leads to nonalcoholic fatty liver diseases (NAFLD). NAFLD spectrum ranges from a
simple nonalcoholic fatty liver (steatosis) to steatohepatitis (NASH) and cirrhosis. Insulin resistant
metabolic disorder and subsequent inflammation are the major pathogenesis for development of the
diseases, but the details of the mechanisms are not fully understood. Most studies have focused on the
role of free fatty acid-mediated lipotoxicity. It has however been shown that there is widespread dysregulation
of lipid metabolism in NAFLD and, specifically, there are major perturbations in cholesterol metabolism. The
potential mechanisms by which such perturbations may lead to liver diseases remain unknown. This gap in
the field is a major barrier towards understanding the role of cholesterol metabolites in the pathogenesis of
NASH and leveraging this information to develop novel therapies for NAFLD.
 We recently identified novel regulatory cholesterol metabolites, 25HC3S and 25HCDS, in normal
human plasma and liver tissues. Administration of the metabolites or increase in expression of
hydroxysterol sulfotransferase (SULT2B1b, the key enzyme for the synthesis of these metabolites)
decreases lipid accumulation in serum and liver tissues. This proposal focuses on the role of the
metabolites in the development of NAFLD. Hypothesis: Based on our strong preliminary data, we
propose that decreases in SULT2B1b activity with consequent decreases in 25HC3S/25HCDS promote
hepatic steatosis by (1) fail to inhibit the pro-lipogenic transcriptional factor sterol response element
binding proteins (SREBPs) and (2) decrease expression and activity of the peroxisome proliferator-
activated receptor- (PPAR) via epigenomic regulation, activating histone deacetylase (SirT1). We will test
the hypothesis by the following specific aims: 1) To elucidate the biochemical mechanism by which the
cholesterol metabolites regulate lipid metabolism and inflammatory responses. 2) To explore the role of
SULT2B1b in development of NALFD in vitro in free fatty acid-induced and in vivo high fat diet-induced NALFD
models. 3) To test the potential of the cholesterol metabolites to prevent/reverse hepatic lipid accumulation
in NAFLD animal models. The overall goal of this proposal is to understand the molecular mechanisms
of oxysterol sulfation involved in the coordinate regulation of hepatocyte lipid metabolism and
inflammatory responses, and to explore its potential clinical utility as a treatment for NAFLD.

## Key facts

- **NIH application ID:** 9815353
- **Project number:** 5I01BX003656-02
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** SHUNLIN REN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815353

## Citation

> US National Institutes of Health, RePORTER application 9815353, Study the role of oxysterol sulfates in NAFLD development (5I01BX003656-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9815353. Licensed CC0.

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