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An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis
- Source :
- Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020)
- Publication Year :
- 2019
-
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.<br />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.
- Subjects :
- 0301 basic medicine
Male
Cell biology
medicine.drug_class
Physiology
Science
Hypercholesterolemia
General Physics and Astronomy
Organic Anion Transporters, Sodium-Dependent
Cholesterol 7 alpha-hydroxylase
Biochemistry
General Biochemistry, Genetics and Molecular Biology
Article
Cell Line
Bile Acids and Salts
03 medical and health sciences
Mice
0302 clinical medicine
Ileum
medicine
Animals
Humans
lcsh:Science
Cholesterol 7-alpha-Hydroxylase
PI3K/AKT/mTOR pathway
Multidisciplinary
Bile acid
Symporters
Chemistry
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
FGF15
FGF19
General Chemistry
Hep G2 Cells
Fibroblast Growth Factors
Disease Models, Animal
030104 developmental biology
Cholesterol
Liver
FGF15/19
Diet, Western
030220 oncology & carcinogenesis
TFEB
lcsh:Q
Homeostasis
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature communications
- Accession number :
- edsair.doi.dedup.....e0c814acdeaac006cbadf1689efde423