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

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.
Yifeng Wang 1,  Sumedha Gunewardena 2,  Feng Li 3,  David J Matye 1 4,  Cheng Chen 1,  Xiaojuan Chao 1,  Taeyoon Jung 1,  Yuxia Zhang 1,  Maciej Czerwiński 5,  Hong-Min Ni 1,  Wen-Xing Ding 1,  Tiangang Li 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 2 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 4 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
  • 5 Sekisui XenoTech LLC, Kansas City, KS, 66103, USA.
  • 6 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. [email protected].
PMID: 32681035 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.

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