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

Award Number: R01DK118064
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Novel FXR-dependent Molecular Mechanisms in the Regulation of Liver Metabolism - 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, our discoveries suggest that targeting specific genes that are downstream of FXR, either individually or in combination, may hold significant promise for future therapeutic intervention to treat NAFLD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $534,759 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/22/2021	NON-COMPETING CONTINUATION	$481,282
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/29/2022	NON-COMPETING CONTINUATION	$53,477
														Subtotal = $534,759

Issue Date FY: 2021 ( Subtotal = $534,759 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/17/2020	NON-COMPETING CONTINUATION	$481,282
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/1/2021	NON-COMPETING CONTINUATION	$53,477
														Subtotal = $534,759

Issue Date FY: 2020 ( Subtotal = $534,759 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/20/2019	NON-COMPETING CONTINUATION	$481,282
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/10/2020	NON-COMPETING CONTINUATION	$53,477
														Subtotal = $534,759

Issue Date FY: 2019 ( Subtotal = $534,759 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/7/2019	NEW	$534,759
														Subtotal = $534,759

Grand Total All Awards = $2,139,036

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

Award Number: R01DK118064

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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