An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis

Abstract

Bile acid synthesis plays a key role in regulating whole body cholesterol homeostasis. Transcriptional factor EB (TFEB) is a nutrient and stress-sensing transcriptional factor that promotes lysosomal biogenesis. Here we report a role of TFEB in regulating hepatic bile acid synthesis. We show that TFEB induces cholesterol 7α-hydroxylase (CYP7A1) in human hepatocytes and mouse livers and prevents hepatic cholesterol accumulation and hypercholesterolemia in Western diet-fed mice. Furthermore, we find that cholesterol-induced lysosomal stress feed-forward activates TFEB via promoting TFEB nuclear translocation, while bile acid-induced fibroblast growth factor 19 (FGF19), acting via mTOR/ERK signaling and TFEB phosphorylation, feedback inhibits TFEB nuclear translocation in hepatocytes. Consistently, blocking intestinal bile acid uptake by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic TFEB nuclear localization and improves cholesterol homeostasis in Western diet-fed mice. This study has identified a TFEB-mediated gut-liver signaling axis that regulates hepatic cholesterol and bile acid homeostasis.

Full citation:

Wang, Yifeng, et al. “An FGF15/19-TFEB Regulatory Loop Controls Hepatic Cholesterol and Bile Acid Homeostasis.” Nature Communications, vol. 11, no. 1, 2020, doi:10.1038/s41467-020-17363-6.

Contributing authors include Director of Scientific Communications, Dr. Maciej Czerwinski

Authors: Yifeng Wang, Sumedha Gunewardena, Feng Li, Jie Wang, Cheng Chen