Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Targeting Intracellular Cholesterol Distribution: Mechanisms and Therapeutic Strategies for Metabolic dysfunction-associated steatotic liver disease (MASLD)

Award Number: R01DK140312
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: 03/12/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

Group Awards By:

View Award Description

Targeting Intracellular Cholesterol Distribution: Mechanisms and Therapeutic Strategies for Metabolic dysfunction-associated steatotic liver disease (MASLD) - PROJECT SUMMARY: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant public health concern, affecting up to 25% of the U.S. population. While cholesterol homeostasis is known to influence MASLD pathogenesis, the precise mechanisms by which excess cholesterol exacerbates hepatic lipid accumulation remain unclear. Our laboratory has identified the Aster family of proteins (Aster-A, -B, and -C) as critical mediators of cholesterol transport from the plasma membrane (PM) to the endoplasmic reticulum (ER). Notably, Aster-C is selectively expressed in hepatocytes, the primary cell type responsible for lipid accumulation in MASLD. Our preliminary studies demonstrate that loss of Aster-C in hepatocytes protects against diet-induced hepatic steatosis by reducing lipid accumulation, normalizing liver enzyme levels, and decreasing inflammation-related gene expression. Based on new preliminary data and reviewer feedback, this revised application specifically investigates the role of Aster-C in cholesterol-mediated MASLD progression and evaluates the therapeutic potential of Aster-C inhibition. We hypothesize that Aster-C ablation mitigates hepatic steatosis by reducing ER cholesterol accumulation, which suppresses fatty acid uptake and de novo lipogenesis (DNL) through distinct molecular mechanisms. To test this hypothesis, we propose three aims: Aim 1 will determine how Aster-C loss reduces fatty acid uptake in hepatocytes by modulating the Nrf1/Nfe2L1-CD36 pathway. Aim 2 will investigate the impact of Aster-C loss on oxysterol synthesis and LXR-SREBP1c-mediated DNL. Aim 3 will evaluate the therapeutic potential of newly identified Aster-C-specific inhibitors in diet-induced MASLD models through pharmacokinetic and efficacy studies. These studies will elucidate the molecular mechanisms linking intracellular cholesterol transport to MASLD progression and establish Aster-C as a potential therapeutic target for MASLD.


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: 2026 ( Subtotal = $707,062 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/11/2026	NEW	$707,062
														Subtotal = $707,062

Grand Total All Awards = $707,062

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting Intracellular Cholesterol Distribution: Mechanisms and Therapeutic Strategies for Metabolic dysfunction-associated steatotic liver disease (MASLD)

Award Number: R01DK140312

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: 03/12/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer