# Contributions of hepatic and intestinal pathways to cholesterol excretion

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $451,563

## Abstract

7. Project Summary
The elimination of excess cholesterol from the body is essential in maintaining homeostasis and
opposing the development of a number of metabolic diseases, most notably atherosclerotic
cardiovascular disease. Classically, cholesterol elimination is thought to be accomplished by hepatic
metabolism of cholesterol to bile acids and the secretion of both bile acids and cholesterol in the bile.
However, under a number of conditions in which biliary secretion of cholesterol is compromised fecal
excretion is maintained, indicating the presence of a non-biliary, alternate pathway. Previously
published and preliminary studies demonstrate that the proximal small intestine is capable of
secreting cholesterol and that the rate of intestinal cholesterol secretion increases when biliary
cholesterol secretion is reduced. The hypothesis of this proposal is that transintestinal cholesterol
elimination (TICE) is regulated by biliary cholesterol output, by plasma lipoprotein donors, and by an
enterohepatic signaling axis involving bile acids. To date, the contribution of the intestine to
cholesterol excretion has largely been inferred by calculating differences in cholesterol concentrations
in bile among strains of mice or in response to pharmacological agents relative to the changes in fecal
neutral sterols. We have developed a novel surgical procedure to simultaneously measure rates of
biliary and intestinal cholesterol secretion in mice. This will allow us to address, for the first time, the
relative rates of biliary and intestinal cholesterol secretion, track the delivery of cholesterol from
plasma lipoproteins to both the hepatic and intestinal pathway, and better understand how the
intestine adapts to alterations in biliary cholesterol secretion. The aims are to: I) determine the impact
of biliary cholesterol secretion on intestinal cholesterol secretion rates, II) determine the lipoprotein
donors to both the biliary and intestinal pathway under conditions of high and low biliary cholesterol
secretion, and III) determine the impact of bile acid signaling in the intestine on hepatic and intestinal
cholesterol secretion. The accomplishment of these aims will further our understanding of the
intestine as a regulator of cholesterol homeostasis and identify novel regulators of intestinal
cholesterol secretion that may be targeted to promote cholesterol excretion and the removal of excess
cholesterol from the body.

## Key facts

- **NIH application ID:** 9983678
- **Project number:** 5R01DK113625-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Gregory A Graf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,563
- **Award type:** 5
- **Project period:** 2017-09-13 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983678

## Citation

> US National Institutes of Health, RePORTER application 9983678, Contributions of hepatic and intestinal pathways to cholesterol excretion (5R01DK113625-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983678. Licensed CC0.

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