# PPARa and related nuclear receptors in non-alcoholic fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $357,225

## Abstract

PROJECT SUMMARY/ABSTRACT
The epidemic of obesity and type 2 diabetes has increased prevalence of associated cardiometabolic diseases
including elevated serum triglycerides (TGs) and non-alcoholic fatty liver disease (NAFLD). There is resurgent
interest in drugs targeting the hepatic nuclear receptor PPARα. Such fibrate drugs are already used in
hypertriglyceridemia, and there is new appreciation that TGs independently cause atherosclerotic cardiovascular
disease such that lowering TGs reduces risk. Furthermore, PPAR agonists may be among the first drugs
approved for NAFLD. Adverse clinical outcomes in NAFLD like cirrhotic liver failure, hepatocellular carcinoma,
and liver-related death are all closely linked to hepatic fibrosis. Our preliminary data in a NAFLD mouse model
show unexpectedly that PPARα deficiency and PPARα agonist treatment both fail to change hepatic steatosis,
but markedly affect fibrosis (increasing and decreasing it, respectively). PPARα functions in hepatocytes to bind
regulatory DNA and affect expression of key genes in lipid metabolism. The related nuclear receptor HNF4α is
not a drug target, yet regulates similar genes and binds similar regulatory DNA. We hypothesize that the interplay
of PPARα and HNF4α in DNA binding affects hepatocyte gene regulation, relevant to the pathogenesis and
therapeutics of NAFLD. Our experiments probe genome-wide nuclear receptor binding sites and gene regulation,
in normal and steatotic livers, basally and in response to drugs. Aim 1 defines the interdependency of PPARα
and HNF4α in liver gene regulation, using mouse models deficient in either or both. Aim 2 extends these studies
of PPARα and HNF4α to NAFLD, in both mouse models and human biospecimens. Aim 3 deploys the powerful
tools of genetics to characterize PPARα and HNF4α interplay in sequence-specific DNA binding. By comparing
inbred mouse strains, natural polymorphisms affecting binding motifs will reveal mechanisms for selective and
common DNA binding by PPARα and HNF4α. In human liver samples, we will test the hypothesis that that non-
coding genetic variants in PPARα/HNF4α genomic binding sites underlie some differences among people in TG
levels, NAFLD, and response of these to PPARα agonist drugs. Beyond this potential clinical relevance, these
studies use innovative genomic and genetic approaches to address key unanswered questions in the biology of
PPARα, including its interplay with related nuclear receptors.

## Key facts

- **NIH application ID:** 10210669
- **Project number:** 1R01DK125573-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MITCHELL A. LAZAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,225
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210669

## Citation

> US National Institutes of Health, RePORTER application 10210669, PPARa and related nuclear receptors in non-alcoholic fatty liver disease (1R01DK125573-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210669. Licensed CC0.

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