# Hepatocyte PPARgamma regulated mechanisms in NAFLD and lipid homeostasis

> **NIH NIH K01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $136,521

## Abstract

Abstract – Non-alcoholic fatty liver disease (NAFLD) encompasses non-alcoholic fatty liver (NAFL/steatosis)
to non-alcoholic steatohepatitis (NASH). Although simple steatosis can be “benign”, it is an independent risk
factor for NASH development. Thiazolidinediones (TZD) are PPARγ agonists used to reduce steatosis in
diabetics with NASH. However, the impact of TZD on steatosis is limited, without any resolution of fibrosis.
The antisteatotic actions of TZD may be due to reduced insulin resistance in both humans and mouse models.
However, TZD-mediated activation of hepatocyte PPARγ may offset the putative antisteatogenic effects of TZD
and prevent any reduction in fibrosis. This is based on the following observations: 1) Hepatic PPARγ
dramatically increases in NAFLD; 2) TZD exacerbate steatosis in a hepatocyte PPARγ-dependent fashion in
mice; and 3) Clinically, the antisteatogenic effect of TZD is limited to the reduction in insulin resistance. To
date, the impact of hepatocyte PPARγ-regulated lipid metabolism on NAFLD is poorly understood. Therefore
we have knocked-down hepatocyte PPARγ (>99.5%) in adult PPARγfl/fl mice using an adeno-associated viral
vector that express Cre recombinase only in hepatocytes (AAV8-TBGp-Cre). Loss of hepatocyte PPARγ
reduced diet-induced steatosis, therefore in SA#1 studies are proposed to determine how loss of
hepatocyte PPARγ prevents diet-induced NAFLD. We hypothesize that the reduction in Cd36-mediated FA
uptake and/or Mogat1-mediated FA re-esterification, observed after loss of hepatocyte PPARγ, are critical for
the reduction in steatosis and subsequent development of NASH. To test this hypothesis, adult PPARγfl/fl mice
will be fed a high fat, high cholesterol, high sucrose diet (HF-HC-HSD) known to induce steatosis (8 weeks of
diet) and NASH (27 weeks of diet). Hepatocyte PPARγ will be knocked down, without or with restoration of
Cd36 (FA translocase) or Mogat1 (Monoacylglycerol acyltransferase). Hepatic FA uptake, MOGAT activity, FA
composition of triacylglycerols (TAG), diacylglycerols (DAG), and monoacylglycerols (MAG)], gene expression
and liver and systemic metabolic pathophysiology will be assessed. Although loss of hepatocyte PPARγ
reduced steatosis, it led to postprandial dyslipidemia. Therefore in SA#2 studies are proposed to determine
the mechanism(s) that promotes postprandial dyslipidemia after loss of hepatocyte PPARγ. We
hypothesize that dyslipidemia associated with specific loss of hepatocyte PPARγ is due to enhanced intestinal
fat absorption which will be tested by feeding mice a diet containing a nonabsorbable fat or after oral delivery
of radio-labeled TAG in the presence of tyloxapol. We also hypothesize that changes in tissue-specific TAG
uptake is impaired after loss of hepatocyte PPARγ, which will be tested by assessing liver, heart, muscle and
adipose tissue uptake of radio-labeled TAG delivered by oral gavage or iv (to factor out changes in intestinal
uptake). The results derived from t...

## Key facts

- **NIH application ID:** 9841395
- **Project number:** 5K01DK115525-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jose Cordoba-Chacon
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $136,521
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841395

## Citation

> US National Institutes of Health, RePORTER application 9841395, Hepatocyte PPARgamma regulated mechanisms in NAFLD and lipid homeostasis (5K01DK115525-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841395. Licensed CC0.

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