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

Yifeng Wang, Sumedha Gunewardena, Feng Li, David J. Matye, Cheng Chen, Xiaojuan Chao, Taeyoon Jung, Yuxia Zhang, Maciej Czerwiński, Hong-Min Ni, Wen-Xing Ding and Tiangang Li ()
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Yifeng Wang: University of Kansas Medical Center
Sumedha Gunewardena: University of Kansas Medical Center
Feng Li: Baylor College of Medicine
David J. Matye: University of Kansas Medical Center
Cheng Chen: University of Kansas Medical Center
Xiaojuan Chao: University of Kansas Medical Center
Taeyoon Jung: University of Kansas Medical Center
Yuxia Zhang: University of Kansas Medical Center
Maciej Czerwiński: Sekisui XenoTech LLC
Hong-Min Ni: University of Kansas Medical Center
Wen-Xing Ding: University of Kansas Medical Center
Tiangang Li: University of Oklahoma Health Sciences Center

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17363-6

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