# ATP Binding Cassette Transporters in Health and Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $608,139

## Abstract

ABSTRACT
Metabolic and chronic liver diseases are among the leading causes of death in the US. The liver is a central hub
that coordinately regulates the metabolism of many nutrients, including lipids. The liver does not store lipids in
the long-term, and lipid accumulation in the liver results in different diseases. Triglyceride accumulation in the
liver causes steatosis which can progress to non-alcoholic steatohepatitis (NASH), both part of the non-alcoholic
fatty liver disease (NAFLD) spectrum. Accumulation of bile acids in the liver because of viral infections, alcohol
use or more advanced liver damage causes cholestasis. Identification of the molecular mechanisms of specific
disease-promoting pathways is an essential step before pathways can be safely targeted for disease prevention.
Our studies will further the understanding of the role of peroxisomal ABCD transporters in the liver. We have
used an unbiased systems biology approach to identify new players in the regulation of lipid metabolism in the
liver. Through these methods, we identified the peroxisomal transporter ABCD3 as a novel regulator of hepatic
lipid metabolism. Abcd3−/− mice are partially lethal and loss of ABCD3 in surviving animals alters the hepatic
lipidome and results in hepatomegaly and profoundly reduced biliary bile acids. To study ABCD3 in vivo, we
have developed and validated a novel AAV-CRISPR strategy to disrupt Abcd3 exclusively in the liver, allowing
us to disrupt Abcd3 in adult wild-type mice in a temporal fashion to determine the sequelae of events leading to
the defects observed after loss of ABCD3. Using these tools, we show that acute loss of hepatic ABCD3 in adult
mice is sufficient to recapitulate the dramatic reduction in biliary bile acids. When fed a Western diet (WD), loss
of hepatic ABCD3 results in liver lipid accumulation as well as elevated plasma liver enzymes and bile acids, all
hallmarks of NASH. We have designed two specific aims; in Aim 1 we will test the hypothesis that ABCD3
deficiency results in cholestasis and NASH. In Aim 2, we will identify specific substrates for ABCD3 and test the
hypothesis that peroxisomal lipid defects are pathogenic and key for the development of NASH. Our studies
demonstrate that loss of ABCD3, which is lethal in humans, results in cholestasis and NASH in a setting of
elevated lipid levels. Completion of these studies will further the understanding of the role of peroxisomal ABCD
transporters in the liver, and implicate peroxisomal lipid metabolism as an important contributor in the
pathogenesis of NASH.

## Key facts

- **NIH application ID:** 10390366
- **Project number:** 5R01DK128952-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Elizabeth Joanna Tarling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $608,139
- **Award type:** 5
- **Project period:** 2021-04-09 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390366

## Citation

> US National Institutes of Health, RePORTER application 10390366, ATP Binding Cassette Transporters in Health and Disease (5R01DK128952-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10390366. Licensed CC0.

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