Non-alcoholic fatty liver disease represents a group of conditions associated with excessive lipid accumulation in hepatocytes. Hepatic steatosis affects almost 30% of adults and imposes a major health burden on American society. Non-alcoholic fatty liver disease increases morbidity and mortality associated with injury or physiological stress, and thus is a concern for all medical disciplines. Our preliminary studies have identified a novel molecular pathway and novel cellular mechanisms that couple long-term energy supply to steatosis and injury. Our studies demonstrate for the first time that a member of the leucine-rich repeat-containing G protein- coupled receptors, LGR4, is expressed in hepatocytes. R-spondin family proteins were recently identified as ligands for LGR4. Our preliminary data also indicate that R-spondin1 is produced by hepatocytes and that R- spondin1-LGR4 signaling is present in the liver. Distinct from classical G protein-coupled receptors which act via G proteins, hepatic LGR4 functions mainly through Wnt/?-catenin signaling. Further, preliminary studies indicate that the mechanistic target of rapamycin complex 1 (mTORC1) in liver couples long-term nutrient status to R-spondin1-LGR4 expression. Steatosis down regulates hepatic R- spondin1/LGR4 and renders hepatic tissue more vulnerable to injury. We propose to investigate the function of the hepatic R-spondin1-LGR4 system using cell biological and transgenic techniques. Completion of this proposal will advance a completely new area of hepatic physiology and will provide novel insights into to liver injury.

Public Health Relevance

While it is known that steatotic livers are particularly vulnerable to ischemic-reperfusion injury, incomplete understanding of the molecular and cellular mechanisms underlying injury limits development of strategies for effective prevention and treatment of injury in steatotic liver. This proposal will investigate the function of the Rspondin1 and its receptor named LGR4 in liver cells using cell biological and transgenic techniques. The information generated from this project will provide new insights relevant to prevention and treatment strategies for liver injury in patients with non-alcoholic fatty liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK110273-02
Application #
9435119
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Sherker, Averell H
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Li, Ziru; Zhang, Jing; Mulholland, Michael et al. (2017) mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-?B pathway. FASEB J 31:3018-3026