# Regulation of Hepatic P450s by Anti-Cholesterol Drugs

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $406,224

## Abstract

Cardiovascular diseases, which include coronary artery disease and stroke, are the leading causes of
morbidity and mortality in the United States. Elevated levels of LDL cholesterol are a major risk factor for
coronary artery disease, and more than 30% of American adults and 7% of adolescents have high LDL
cholesterol levels. There is a log-linear relationship between blood cholesterol level and mortality due to
coronary artery disease, which indicates the benefit of cholesterol reduction regardless of the starting level.
The liver plays a dominant role in cholesterol metabolism, so many pharmacological approaches to lower
cholesterol target the liver. The “statins” have proven effective at reducing cholesterol levels and mortality due
to coronary artery disease, and they are therefore among the most widely used drugs in the United States.
However, statins also produce adverse effects and undergo drug-drug interactions. Our goal is to understand
the spectrum of mechanisms by which statins and other drugs that interfere with cholesterol metabolism
regulate hepatic processes. This project focuses on a non-therapeutic consequence of cholesterol synthesis
inhibition that involves an interaction with the constitutive androstane receptor (CAR), a xenobiotic-sensing
regulator of drug, glucose, and lipid metabolism. This interaction does not occur in rodent hepatocytes,
emphasizing the need to study the process in human hepatic systems. The hypothesis of this project is that
inhibition of cholesterol biosynthesis suppresses CAR activation and target gene expression in human
hepatocytes and that this effect is mediated through an inhibitory interaction between CAR and sterol
regulatory element binding factor 2 (SREBP2). The specific aims are to (1) define the impact of cholesterol
synthesis inhibition on CAR target gene expression in human hepatocytes in vitro and in vivo and (2) define the
mechanism by which cholesterol synthesis inhibition regulates CAR target gene expression in human hepatic
cells. To investigate the impact of cholesterol synthesis inhibition on CAR-regulated gene expression in a
manner that is directly relevant to humans, the study emphasizes the use of human hepatocytes, both in
primary culture and in a mouse model. The mechanistic studies consider the complexity of different human
CAR isoforms; evaluate the impact of cholesterol synthesis inhibition on CAR expression, activation, and
recruitment to the promoters of target genes; and feature determining how an interaction between CAR and
SREBP2 could underlie the impact of cholesterol synthesis inhibition on CAR activity. The findings of this study
will provide new insight into the fundamental mechanisms by which drugs that inhibit cholesterol biosynthesis
can affect human hepatocellular physiology in a manner that alters xenobiotic-sensing receptor-sensitive
processes. Because these effects emanate from inhibition of the drug's intended target, they are not easily
dissociated from t...

## Key facts

- **NIH application ID:** 9961386
- **Project number:** 5R01HL050710-22
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Thomas A Kocarek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,224
- **Award type:** 5
- **Project period:** 1993-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961386

## Citation

> US National Institutes of Health, RePORTER application 9961386, Regulation of Hepatic P450s by Anti-Cholesterol Drugs (5R01HL050710-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9961386. Licensed CC0.

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