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

• Published in: Nature communications Vol. 11; no. 1; pp. 3612 - 16
• Main Authors: Wang, Yifeng, Gunewardena, Sumedha, Li, Feng, Matye, David J., Chen, Cheng, Chao, Xiaojuan, Jung, Taeyoon, Zhang, Yuxia, Czerwiński, Maciej, Ni, Hong-Min, Ding, Wen-Xing, Li, Tiangang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 49/15; 631/443; 631/45; 631/80; 64/60; 96/95; Acids; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - antagonists & inhibitors; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Bile; Bile Acids and Salts - metabolism; Biosynthesis; Cell Line; Cholesterol; Cholesterol - metabolism; Cholesterol 7-alpha-Hydroxylase - metabolism; Diet; Diet, Western - adverse effects; Disease Models, Animal; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Growth factors; Hep G2 Cells; Hepatocytes; Homeostasis; Humanities and Social Sciences; Humans; Hydroxylase; Hypercholesterolemia; Hypercholesterolemia - etiology; Hypercholesterolemia - metabolism; Hypercholesterolemia - prevention & control; Ileum - drug effects; Ileum - metabolism; Intestine; Liver; Liver - drug effects; Liver - metabolism; Localization; Male; Mice; multidisciplinary; Nuclear transport; Organic Anion Transporters, Sodium-Dependent - antagonists & inhibitors; Phosphorylation; Science; Science (multidisciplinary); Signaling; Symporters - antagonists & inhibitors; Synthesis; TOR protein; Translocation
• DOI: 10.1038/s41467-020-17363-6
• ISSN: 2041-1723

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. TFEB is a transcriptional regulator of lysosomal biogenesis, activated upon starvation or lysosomal stress. Here the authors report that TFEB regulates hepatic bile acid synthesis downstream of FGF19 signaling.