Wednesday, April 24, 2024 4/24/2024

Significance and mechanisms of hepatic ChREBP? induction via post-translational modifications in diet-induced NASH

Award Number: R01DK099593
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Abstract NAFLD is the most common chronic liver disease affecting 10-30% of the general population. Its transition from simple steatosis to non-alcoholic steatohepatitis (NASH) poses a serious health threat due to the eventual progression to cirrhosis and liver failure. Given the fact that liver transplant is the only treatment option for patients at the end stage of NASH, there is an urgent need to understand the molecular mechanisms underlying the development of NASH. So far, both human and animal studies have suggested that chronic suppression of FAO in the liver could be a critical driver in promoting fatty liver disease. Meanwhile, uncontrolled activation of hepatic stellate cells (HSCs) has been identified as the primary source of hepatic fibrogenesis. However, there is a significant knowledge gap regarding whether and how dysregulation of hepatic fatty acid oxidation promotes NASH. Moreover, whether and how hepatic lipid regulators contribute to HSCs activation and liver fibrosis remains unknown. We have gathered evidence hepatic ChREBPa as a novel regulator of fatty acid oxidation in contrast to its canonical role as lipogenic transcriptional factor. Hepatocyte-specific ChREBPa knockout mice are more sensitive to diet induced NASH, whereas hepatic over-expression of ChREBPa protects mice against diet-induced NASH. Our RNA-seq analysis revealed that hepatic deficiency of Chrebpa elevates a panel of pro-fibrogenic factors in the mouse liver after feeding with NASH diet. Our in vitro experiments further demonstrated that Chrebpa-deficient hepatocytes stimulate fibrogenesis of human hepatic stellate cells via secreting factors, suggesting that hepatocyte ChREBPa could influence the microenvironment around hepatic stellate cells and modulate their activities. Based on these intriguing observations, we hypothesize that hepatocyte ChREBPa protects against diet-induced NAFLD/NASH by promoting fatty acid oxidation in hepatocytes and suppressing hepatic stellate cells activation. In this study, we propose to test our hypothesis in three aims: Aim 1 is to examine whether hepatic Chrebpa protects against diet-induced NAFLD/NASH via maintaining fatty acid oxidation pathway. Aim 2 is to determine whether hepatocyte ChREBPa suppresses hepatic stellate cell activation via secreting profibrogenic factors. Aim 3 is to dissect out the signaling and degradation pathways that control ChREBPa expression and activity during NASH. The completion of the proposed study would elucidate in- depth molecular mechanisms of how ChREBPa protects against diet-induced NASH, identify ChREBPa-associated risk factors, and shed light on novel strategies for the prevention and treatment diet-induced NASH.


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: 2023 ( Subtotal = $571,102 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	5/10/2023	NON-COMPETING CONTINUATION	$571,102
														Subtotal = $571,102

Issue Date FY: 2022 ( Subtotal = $571,102 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/9/2022	NON-COMPETING CONTINUATION	$571,102
														Subtotal = $571,102

Issue Date FY: 2021 ( Subtotal = $571,102 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	9/22/2021	COMPETING CONTINUATION	$571,102
														Subtotal = $571,102

Issue Date FY: 2020 ( Subtotal = -$21 )
2020	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/14/2020	NON-COMPETING CONTINUATION	-$21
														Subtotal = -$21

Issue Date FY: 2018 ( Subtotal = $337,125 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/18/2018	NON-COMPETING CONTINUATION	$33,713
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/21/2018	NON-COMPETING CONTINUATION	$303,412
														Subtotal = $337,125

Issue Date FY: 2017 ( Subtotal = $337,125 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/23/2017	NON-COMPETING CONTINUATION	$303,412
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/16/2017	NON-COMPETING CONTINUATION	$33,713
														Subtotal = $337,125

Issue Date FY: 2016 ( Subtotal = $337,125 )
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/25/2016	NON-COMPETING CONTINUATION	$337,125
														Subtotal = $337,125

Issue Date FY: 2015 ( Subtotal = $337,397 )
2015	2015	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/26/2015	NON-COMPETING CONTINUATION	$337,397
														Subtotal = $337,397

Issue Date FY: 2014 ( Subtotal = $338,213 )
2014	2014	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/10/2014	NEW	$338,213
														Subtotal = $338,213

Grand Total All Awards = $3,400,270

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Significance and mechanisms of hepatic ChREBP? induction via post-translational modifications in diet-induced NASH

Award Number: R01DK099593

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer