# Coactivator P300 promotes hepatic steatosis in obesity

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $539,185

## Abstract

Obesity, which has reached epidemic proportions worldwide, is associated with an increased risk of numerous
metabolic abnormalities including nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). NAFLD
is increasingly common, and now affects over 30% of the population in the USA. Insulin resistance is a hallmark
of type 2 diabetes and obesity, and excessive accumulation of triglycerides is a hallmark of NAFLD. Because
intact insulin signaling is required for lipogenesis, the defect in insulin signaling should reduce hepatic triglyceride
content; however, patients with obesity and type 2 diabetes commonly have nonalcoholic fatty liver disease
(NAFLD), and the majority of patients with NAFLD are also obese and/or have T2D. The underlying mechanisms
leading to the paradoxical co-occurrence of hepatic steatosis and insulin resistance are not well understood.
Previous studies have shown that overexpression of the deacetylase Sirtuin 1 or treatment with resveratrol, a
Sirtuin 1 activator, not only improved hepatic steatosis, but also restored insulin sensitivity in tissues with insulin
resistance. These results suggest that an acetyltransferase can antagonize Sirtuin 1’s activity, causing hepatic
steatosis and insulin resistance. We observed a significant increase in hepatic acetyltransferase P300’s protein
levels in high-fat diet (HFD) fed mice and ob/ob mice through the IRE1-XBP1s pathway in the endoplasmic
reticulum stress response. Depletion of P300 or inhibition of P300 acetyltransferase activity decreased lipogenic
gene expression and increased insulin sensitivity. Therefore, P300 uniquely increases lipogenesis and disrupts
insulin signaling in the liver of obesity. We will assess the role of elevated P300 in promoting hepatic lipogenesis
in Aim 1. We will define the molecular mechanisms of P300’s promotion of hepatic steatosis in Aim 2. We propose
to determine whether P300 acetyltransferase activity is a therapeutic target for obesity/T2D in Aim 3. We believe
that P300 plays an important role in the development of NAFLD and insulin resistance, linking inflammatory and
metabolic diseases.

## Key facts

- **NIH application ID:** 10131027
- **Project number:** 5R01DK120309-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ling He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $539,185
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131027

## Citation

> US National Institutes of Health, RePORTER application 10131027, Coactivator P300 promotes hepatic steatosis in obesity (5R01DK120309-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10131027. Licensed CC0.

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