# Bile acid-mediated control of lipid absorption and fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $644,174

## Abstract

ABSTRACT
The non-alcoholic fatty liver disease (NAFLD) spectrum is now the most common cause of liver diseases, and
responsible for the biggest proportion of liver transplants. The liver is a central hub that coordinately regulates
the metabolism of many nutrients, including lipids. The liver is not designed for long-term storage lipids, instead
acting as a distributor of lipids with high short-term storage capacity. Long-term lipid accumulation in the liver, in
the form of triglycerides causes steatosis which can progress to non-alcoholic steatohepatitis (NASH), both of
which are part of the NAFLD spectrum. Identification of the molecular mechanisms of pathways that control lipid
metabolism, both systemic and liver specific are essential for the discovery of disease-preventing therapeutic
targets. Bile acids are both signaling molecules and detergents that facilitate lipid absorption in the gut. While
much has been studied in recent years about bile acid signaling, the role of bile acids as detergents that facilitate
the absorption of different fatty acids has been less well studied. We recently showed activation of the bile acid
receptor FXR reduces liver lipid accumulation in part due to lowering of bile acid-mediated lipid absorption. To
determine how bile acids alter the absorption of different fatty acids, we have developed and validated a novel
AAV-CRISPR strategy to disrupt specific bile acid metabolism genes exclusively in the liver. Using these tools,
we show that specific modulations in the total amount and/or composition of bile acids has profound effects on
liver steatosis. To measure lipid absorption quantitatively and accurately, we have established a non-invasive
mass spectrometry-based approach to measure the absorption of different dietary fatty acids in the intestine in
vivo. We have also developed complimentary imaging modalities to visualize lipids in the intestine. Using these
assays, we have shown that modulating bile acids dramatically reduces lipid absorption but retain preferential
absorption of polyunsaturated fatty acids. These changes contrast with inhibition of lipases in the gut (using
Orlistat) which reduced the absorption of all fatty acids. Here, we have designed two specific aims utilizing a
combination of in vivo and in vitro systems to test the hypothesis targeting bile acids results in specific and
beneficial changes in lipid absorption that are protective against NAFLD or are pathogenic and drive liver fibrosis.
Completion of these studies will further the understanding of the role of bile acids as detergents, implicate bile
acid metabolism as an important contributor in the pathogenesis of NAFLD/NASH, and potentially establish new
therapeutic strategies to target NAFLD.

## Key facts

- **NIH application ID:** 10792162
- **Project number:** 1R01DK138340-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Thomas A Vallim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $644,174
- **Award type:** 1
- **Project period:** 2023-12-15 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792162

## Citation

> US National Institutes of Health, RePORTER application 10792162, Bile acid-mediated control of lipid absorption and fatty liver disease (1R01DK138340-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10792162. Licensed CC0.

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