# Novel FXR-dependent Molecular Mechanisms in the Regulation of Liver Metabolism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $534,759

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver disease, and affects almost one third
of adults. Progression from early stages such as steatosis to non-alcoholic steatohepatitis (NASH) requires both
the accumulation of triglyceride (TAG) and hepatocyte injury. NASH can be reversed, yet there are limited
therapeutic options available. Recent clinical trials have shown that targeting the nuclear receptor FXR holds
significant therapeutic promise to treat NASH. FXR activation can be beneficial because FXR is thought to
decrease lipogenesis in the liver through an FXR SHP SREBP1C pathway. In the current application, we
challenge this paradigm. We have used the potent synthetic and specific FXR agonist GSK2324 to show that
FXR activation reduces both liver TAG levels and lipid synthesis in both chow and western diet (WD)-fed wild-
type, but not Fxr–/– mice. We then show that GSK2324 treatment reduces TAG levels in the livers of Shp–/– and
Srebp1c–/– mice, suggesting these two genes are not essential for the FXR-dependent decrease in hepatic TAG
levels, at least in chow-fed mice. We have used lipidomic analysis to show that FXR activation results in selective
decreases in specific TAG species. We have also used in vivo labeling techniques to measure newly synthesized
lipids, and show that FXR activation selectively alters lipid synthesis. Gene expression analysis supports and
explains these specific changes in TAG species, and led us to identify 2 key lipid metabolism mRNAs that are
potently reduced in wild-type, Shp–/– and Srebp1c–/– mice but not Fxr–/– mice treated with GSK2324. We have
also used a novel non-invasive method to show that FXR activation reduces absorption of dietary lipids. We
have now designed two specific aims to determine the molecular mechanisms involved in the reduction of hepatic
TAGs following FXR activation. We will use in vivo labeling and lipidomic analysis and various KO mice to
determine whether intestinal or hepatic FXR, Shp or Srebp1c are required for FXR-dependent changes in hepatic
lipid synthesis and intestinal lipid absorption in a model for NAFLD. We will also determine the molecular
mechanism involved in the repression of the two key lipid metabolism genes following FXR activation. Our
preliminary data suggest that a new FXR target gene, that we recently identified, promotes the degradation of
mRNAs encoding the two key lipid genes. Finally, we will use AAV-dependent expression of these two genes,
to determine if overexpression can, either alone or in combination, prevent the decrease in hepatic TAG species
following FXR activation. We will also determine whether the FXR-dependent decrease in lipid absorption can
be attenuated by increasing the bile acid pool size. Our studies will provide new insights into the mechanisms
by which FXR activation alters lipid metabolism. This is likely to be important since FXR agonists are currently
being used clinically. Further, o...

## Key facts

- **NIH application ID:** 9889118
- **Project number:** 5R01DK118064-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Peter A Edwards
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $534,759
- **Award type:** 5
- **Project period:** 2019-03-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889118

## Citation

> US National Institutes of Health, RePORTER application 9889118, Novel FXR-dependent Molecular Mechanisms in the Regulation of Liver Metabolism (5R01DK118064-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9889118. Licensed CC0.

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