# Hepatocyte Abca1, cholesterol trafficking, and lipid mobilization

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $491,586

## Abstract

Abstract- This R01 renewal seeks to continue the PI's creative, productive, and significant research program,
which has enjoyed uninterrupted NIH funding since 1996, focused on lipid/lipoprotein metabolism in the
pathogenesis of cardiovascular disease (CVD) and cardiometabolic disease (CMD). For over 15 years, the PI's
research program has focused on ATP binding cassette transporter A1 (Abca1) and lipid and lipoprotein
metabolism using tissue/cell-specific Abca1 knockout mice. Studies in hepatocyte-specific Abca1 knockout
(HSKO) mice provided novel mechanistic insights into how hepatic Abca1 impacts the production and
catabolism of all three major classes of plasma lipoproteins (VLDL, LDL, HDL) that contribute to CVD and
CMD. Despite the massive (~80%) drop in plasma HDL relative to control mice, hyperlipidemic HSKO mice
maintained macrophage reverse cholesterol transport and had decreased aortic root atherosclerosis compared
to controls. HSKO mice also had increased plasma HDL cholesterol transport into the feces, decreased
hepatic insulin signaling and de novo lipogenesis (DNL), increased mitochondrial respiration, increased LDL
receptor expression, and increased hepatic VLDL triglyceride secretion. This unique phenotype was
associated with diminished antegrade trafficking of lysosomal free cholesterol (FC) to the plasma membrane of
hepatocytes, with no differences in total hepatic lipid mass between HSKO and control mice. Based on this
work, our global hypothesis is that targeted deletion of hepatocyte Abca1 enhances hepatocyte retrograde
FC redistribution from the plasma membrane to intracellular compartments, reprogramming insulin-mediated
anabolism towards a coordinated catabolic program that reduces hepatic DNL, improves mitochondrial
metabolism, and increases TG secretion, thereby decreasing hepatic steatosis when mice are stressed with a
high-fat diet. This metabolic reprogramming in the absence of hepatic Abca1 results in a novel form of
selective insulin resistance in HSKO mice, in which hepatic DNL is suppressed, but gluconeogenesis is
appropriately downregulated by insulin. Future studies will address gaps in knowledge and barriers to
progress, including: Specific aim 1) how Abca1 deletion alters FC distribution (or trafficking) among the
plasma membrane, endoplasmic reticulum, and other organelles; Specific aim 2a) how insulin signaling and
endoplasmic reticulum FC interact to activate Srebp1c; and Specific aim 2b) whether loss of Abca1 leads to
increased mitochondria FC and/or lysophospholipid that improves mitochondrial respiration. Our proposed
studies will build a more comprehensive and expansive model for Abca1 as a central control point of metabolic
homeostasis and propel our previous 5-year discoveries in new directions, thereby advancing the field.
Impact- Our studies will continue generating new discoveries regarding regulation of hepatic lipogenesis and
the emerging role of Abca1 and FC trafficking in reprogramming hepatic...

## Key facts

- **NIH application ID:** 9839643
- **Project number:** 5R01HL119962-07
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** JOHN Stephen PARKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,586
- **Award type:** 5
- **Project period:** 2013-07-23 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839643

## Citation

> US National Institutes of Health, RePORTER application 9839643, Hepatocyte Abca1, cholesterol trafficking, and lipid mobilization (5R01HL119962-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9839643. Licensed CC0.

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