# R-spondin1-LGR4 Signaling and Ischemia/Reperfusion Injury in Steatotic Liver

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $411,384

## Abstract

Project Summary
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/β-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.

## Key facts

- **NIH application ID:** 9896813
- **Project number:** 5R01DK110273-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MICHAEL W. MULHOLLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,384
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896813

## Citation

> US National Institutes of Health, RePORTER application 9896813, R-spondin1-LGR4 Signaling and Ischemia/Reperfusion Injury in Steatotic Liver (5R01DK110273-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896813. Licensed CC0.

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