# Protein inclusions in non-alcoholic steatohepatitis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $351,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-alcoholic fatty liver disease (NAFLD), typically associated with overnutrition and obesity, is one of the
most common liver diseases, both in the U.S. and worldwide, with a prevalence of 20-30%. During obesity and
NAFLD, lipotoxic injuries to hepatocytes can induce the formation of protein inclusions consisting of
p62/SQSTM1 and ubiquitinated proteins. These inclusions can contribute to the pathological progression of
NAFLD to more severe forms of liver diseases, such as non-alcoholic steatohepatitis (NASH) and
hepatocellular carcinoma (HCC). However, we currently do not have any mechanistic understanding of how
lipotoxicity stimulates protein inclusion formation during obesity and NASH, and how this pathway plays a
pathogenetic role during NASH-associated HCC progression. Our goal in this project is to mechanistically
understand how protein inclusions are formed during obesity and how they contribute to the progression of
NASH-HCC pathologies. Our central hypothesis is that TBK1, a protein kinase activated upon lipotoxic insults
during obesity, phosphorylates p62 and that this phosphorylation is an important pathogenetic event that
contributes to protein inclusion body formation and promoting HCC development. The scientific premise
supporting our research, provided by recently published findings and our own preliminary data, includes (1)
activation of hepatic TBK1 during obesity, (2) critical role of p62 in NASH-to-HCC progression, (3) genetic
requirement of TBK1 in obesity-induced p62 phosphorylation and accumulation, and (4) strong impact of
obesity and lipotoxicity on HCC progression. Based on these findings, we further propose to investigate how
TBK1 is activated during obesity (Aim 1) and whether and how the TBK1-mediated p62 control contributes to
progression of NASH to HCC (Aim 2). With respect to expected outcomes, the work proposed in aims 1 and 2
will result in delineation of a signaling pathway that mediates formation of insoluble protein inclusions upon
lipotoxic insults and show its pathological relevance in NASH-associated HCC. Such results are expected to
have an important positive impact, because this new knowledge may lead to development of innovative
therapeutic rationale for NASH-associated HCC, by pharmacological inhibition of the identified pathway
components.

## Key facts

- **NIH application ID:** 9997680
- **Project number:** 5R01DK114131-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jun Hee Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997680

## Citation

> US National Institutes of Health, RePORTER application 9997680, Protein inclusions in non-alcoholic steatohepatitis (5R01DK114131-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997680. Licensed CC0.

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