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
  • 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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