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

Nature Communications
Yifeng WangTiangang Li

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.

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Citations

Sep 18, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Ivo P van de PeppelJohan W Jonker
Dec 1, 2020·Molecular Oncology·Elena AstaninaGabriella Doronzo
Mar 9, 2021·Frontiers in Physiology·Manman LiLiming Yang
Apr 10, 2021·Oxidative Medicine and Cellular Longevity·Xiao XiaoYizhen Wang
May 10, 2021·Cellular and Molecular Gastroenterology and Hepatology·David J MatyeTiangang Li
Jun 15, 2021·Molecular Aspects of Medicine·Hui QianWen-Xing Ding

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Methods Mentioned

BETA
immunoprecipitation
ChIP
nuclear
confocal microscopy
nuclear translocation
transgenic
electrophoresis
PCR
transfection
Assay

Clinical Trials Mentioned

NCT02787304

Software Mentioned

Metabolon
CLEAR
GraphPad Prism
ImageJ
MATLAB

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