# Significance and mechanisms of hepatic ChREBPα induction via post-translational modifications in diet-induced NASH

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $548,258

## Abstract

Abstract
NAFLD is the most common chronic liver disease affecting 10-30% of the general population. Its
transition from simple steatosis to non-alcoholic steatohepatitis (NASH) poses a serious health
threat due to the eventual progression to cirrhosis and liver failure. Given the fact that liver
transplant is the only treatment option for patients at the end stage of NASH, there is an urgent
need to understand the molecular mechanisms underlying the development of NASH. So far,
both human and animal studies have suggested that chronic suppression of FAO in the liver
could be a critical driver in promoting fatty liver disease. Meanwhile, uncontrolled activation of
hepatic stellate cells (HSCs) has been identified as the primary source of hepatic fibrogenesis.
However, there is a significant knowledge gap regarding whether and how dysregulation of
hepatic fatty acid oxidation promotes NASH. Moreover, whether and how hepatic lipid regulators
contribute to HSCs activation and liver fibrosis remains unknown. We have gathered evidence
hepatic ChREBPα as a novel regulator of fatty acid oxidation in contrast to its canonical role as
lipogenic transcriptional factor. Hepatocyte-specific ChREBPα knockout mice are more sensitive
to diet induced NASH, whereas hepatic over-expression of ChREBPα protects mice against
diet-induced NASH. Our RNA-seq analysis revealed that hepatic deficiency of Chrebpα elevates
a panel of pro-fibrogenic factors in the mouse liver after feeding with NASH diet. Our in vitro
experiments further demonstrated that Chrebpα-deficient hepatocytes stimulate fibrogenesis of
human hepatic stellate cells via secreting factors, suggesting that hepatocyte ChREBPα could
influence the microenvironment around hepatic stellate cells and modulate their activities.
Based on these intriguing observations, we hypothesize that hepatocyte ChREBPα protects
against diet-induced NAFLD/NASH by promoting fatty acid oxidation in hepatocytes and
suppressing hepatic stellate cells activation. In this study, we propose to test our hypothesis in
three aims: Aim 1 is to examine whether hepatic Chrebpα protects against diet-induced
NAFLD/NASH via maintaining fatty acid oxidation pathway. Aim 2 is to determine whether
hepatocyte ChREBPα suppresses hepatic stellate cell activation via secreting profibrogenic
factors. Aim 3 is to dissect out the signaling and degradation pathways that control ChREBPα
expression and activity during NASH. The completion of the proposed study would elucidate in-
depth molecular mechanisms of how ChREBPα protects against diet-induced NASH, identify
ChREBPα-associated risk factors, and shed light on novel strategies for the prevention and
treatment diet-induced NASH.

## Key facts

- **NIH application ID:** 10839835
- **Project number:** 5R01DK099593-09
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lei Yin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $548,258
- **Award type:** 5
- **Project period:** 2014-04-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839835

## Citation

> US National Institutes of Health, RePORTER application 10839835, Significance and mechanisms of hepatic ChREBPα induction via post-translational modifications in diet-induced NASH (5R01DK099593-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10839835. Licensed CC0.

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