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.

Public Health Relevance

/PUBLIC HEALTH RELEVANCE STATEMENT With an increasing prevalence of overnutrition and a sedentary lifestyle, obesity-associated non-alcoholic fatty liver disease (NAFLD) has become one of the major health problems of people in the United States and around the world. Among NAFLD pathologies, the formation of insoluble protein inclusions in liver cells is characteristic of a damaged liver in both mice and humans, and is the critical marker that distinguishes simple fatty liver from an advanced form of liver diseases such as non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we propose to investigate the mechanism of how these inclusions are produced during NASH and how they contribute to the NASH-associated HCC pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK114131-01A1
Application #
9521931
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2018-09-20
Project End
2021-08-31
Budget Start
2018-09-20
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109