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

Nat Commun. 2020 Jul 17;11(1):3612. doi: 10.1038/s41467-020-17363-6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Bile Acids and Salts / metabolism*
  • Cell Line
  • Cholesterol / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Diet, Western / adverse effects
  • Disease Models, Animal
  • Fibroblast Growth Factors / metabolism*
  • Hep G2 Cells
  • Humans
  • Hypercholesterolemia / etiology
  • Hypercholesterolemia / metabolism
  • Hypercholesterolemia / prevention & control
  • Ileum / drug effects
  • Ileum / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors
  • Symporters / antagonists & inhibitors

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Bile Acids and Salts
  • FGF19 protein, human
  • Organic Anion Transporters, Sodium-Dependent
  • Symporters
  • TFEB protein, human
  • Tcfeb protein, mouse
  • fibroblast growth factor 15, mouse
  • sodium-bile acid cotransporter
  • Fibroblast Growth Factors
  • Cholesterol
  • CYP7A1 protein, human
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse