# (PQ6)Nuclear receptor mechanisms in circadian disruption induced hepatocarcinogenesis

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $489,764

## Abstract

Project Summary
 This application addresses NCI PQ6 on how circadian processes affect tumor development by studying
the role of circadian dysfunction of nuclear receptor pathways in non-alcoholic fatty liver disease (NAFLD)-
induced hepatocellular carcinoma (HCC).
HCC, previously considered a rare cancer in the Western world, has increased 3-fold in incidence since
the 1980s, and is currently the fastest rising cause of cancer-related death in the U.S, due to an increase
in incidence in combination of lack of understanding of its mechanism. The increased HCC risk is coupled
with the prevalence of obesity-related NAFLD, which has recently become the leading risk factor for HCC.
However, no efficient approaches for prevention, early diagnosis, and treatment of NAFLD-induced HCCs
are currently available. The increased risk of NAFLD-related HCC is coupled with population-wide chronic
circadian disruption, a common risk factor of obesity, NAFLD, and cancer in humans. We have recently
established a jet-lagged mouse model following a human nightshift schedule. We found that chronic jet-lag
induces metabolic syndrome, NAFLD, and HCC in wild-type mice following a pathophysiological pathway
strikingly similar to that observed in obese humans, with NAFLD progressing to nonalcoholic
steatohepatitis (NASH) and fibrosis prior to HCC detection. We identified intrahepatic cholestasis as the
key pathophysiological mechanism promoting NAFLD-induced HCC, and demonstrated that circadian
dysregulation of nuclear receptor FXR and CAR pathways is an essential oncogenic mechanism that
drives cholestasis and toxic bile acid signaling to promote the progression from NAFLD to NASH, fibrosis,
and eventually HCC.
In this application, we propose 3 aims. 1) Define the circadian profiles of FXR and CAR controlled hepatic
gene networks and jet-lag induced deregulation signatures of these gene networks. 2) Define the role of
Ctnnb1 and Tp53 and other oncogenic mutations in the progression from jet-lag induced liver premalignant
lesions to HCC and the circadian profiles of gene signatures as well as serum biomarkers associated with
hepatocarcinogenesis. 3) Test the predicted abilities of FXR agonist obeticholic acid (OCA) and CAR
inverse agonist androstanol (ANDR) to prevent jet-lag induced cholestasis and HCC.
These studies will significantly improve our understanding of the role of circadian dysfunction in
spontaneous carcinogenesis in general, and NFALD-induced hepatocarcinogenesis in particular. They will
also illuminate new and exciting avenues to develop novel chronotherapy strategies for prevention and
treatment of NAFLD-induced HCC in humans.

## Key facts

- **NIH application ID:** 9993447
- **Project number:** 5R01CA230848-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** LONING None FU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,764
- **Award type:** 5
- **Project period:** 2018-09-18 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993447

## Citation

> US National Institutes of Health, RePORTER application 9993447, (PQ6)Nuclear receptor mechanisms in circadian disruption induced hepatocarcinogenesis (5R01CA230848-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993447. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*