# Exercise induced regulation of CYP7a1 and bile acid metabolism

> **NIH NIH F32** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $26,593

## Abstract

PROJECT SUMMARY/ABSTRACT
My long-term professional goal is to become a successful, independent scientist with a research program
focused on the integrative physiological response of exercise to identify potential therapeutic targets for the
treatment and/or prevention of metabolic disease. Hepatic steatosis, the excessive storage of fat in the liver, has
become the most common cause of chronic liver disease worldwide. Exercise can treat and/or prevent steatosis
independent of weight status; however, mechanisms remain unclear. In rodents, genetic overexpression of
cholesterol 7 α-hydroxylase (CYP7a1), the rate limiting enzyme for bile acid (BA) synthesis, protects against
diet-induced steatosis and chronic exercise produces a similar phenotype. CYP7a1 is regulated by numerous
mechanisms during both postprandial, and fasting conditions. During postprandial conditions, induction of
CYP7a1 and subsequent BA synthesis increases via insulin-specific inactivation of forkhead box transcription
factor 1 (FoxO1); whereas under fasting conditions, CYP7a1 transcription is regulated by nuclear localization of
transcription factor EB (TFEB). Importantly, exercise enhances and/or restores hepatic insulin action and
increases nuclear localization of TFEB in skeletal muscle. However, it remains unknown if exercise contributes
to elevated and/or improved BA synthesis through these mechanisms. My overall hypothesis is that exercise
protects against diet-induced hepatic steatosis, in part, through enhanced transcriptional regulation of CYP7a1
allowing for increased BA synthesis and fecal BA excretion, which pulls hepatic acetyl-CoA away from de novo
lipogenesis to act as an energetic siphon during chronic nutrient excess (i.e., obesity). I will test this overall
hypothesis by investigating the impact of exercise on BA metabolism, in diet-induced obese mice. In Aim 1, I will
determine whether enhanced hepatic-insulin action induced by acute exercise will increase postprandial
induction of CYP7a1 transcription and subsequent BA synthesis. In Aim 2, I will investigate if nuclear
translocation of TFEB and TFEB induced transcription of CYP7a1 plays a critical role in the long term effects of
exercise to upregulate hepatic BA metabolism and divert excess acetyl-CoA away from de novo lipogenesis and
toward BA synthesis and excretion. These studies will contribute to the identification of mechanisms by which
exercise protects against hepatic steatosis through a novel pathway while also providing an excellent foundation
of training in liver and integrative metabolism.

## Key facts

- **NIH application ID:** 10389485
- **Project number:** 1F32DK130244-01A1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Harrison Daniel Stierwalt
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $26,593
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-01-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389485

## Citation

> US National Institutes of Health, RePORTER application 10389485, Exercise induced regulation of CYP7a1 and bile acid metabolism (1F32DK130244-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10389485. Licensed CC0.

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