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

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.

TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis

“…Extracellular signal-regulated kinase (ERK) phosphorylates the site of TFEB S142 and makes it relocated in the cytoplasm ( Yonekawa et al, 2015 ; Li et al, 2019 ). Phosphorylation of TFEB S142 by mTOR/ERK inhibits nuclear translocation of TFEB in hepatocytes and thus promotes hepatic cholesterol accumulation ( Wang et al, 2020a ). Whereas AKT (protein kinase B) negatively controls TFEB through phosphorylation at S467 ( Palmieri et al, 2017 ).…”

“…This mechanism may contribute to the prevention of hypercholesterolemia and metabolic disorders. Bile acid-induced fibroblast growth factor 19 mediates feedback inhibition of TFEB activity and nuclear translocation via activating the mTOR/ERK pathway and phosphorylating TFEB ( Wang et al, 2020a ).…”

Multifaceted activities of transcription factor EB in cancer onset and progression

“…Conversely, TFEB reduces the expression of enzymes involved in some lipid biosynthetic pathways [69]. However, in mice fed with western diet, TFEB overexpression has been reported to upregulate enzymes involved in cholesterol and bile acid synthesis [70]. In adipose tissue, TFEB expression stimulated by glucose and insulin is necessary to sustain adipocyte differentiation by a mechanisms mediated by Ppar2 [71], which promotes lipogenesis [72].…”

Gut Immunity and Microbiota Dysbiosis Are Associated with Altered Bile Acid Metabolism in LPS‐Challenged Piglets

“…Studies have revealed that primary BAs synthesized in the liver can be transformed into secondary BAs by the metabolic activities of enteric anaerobic bacteria [ 22 ]. At the terminal ileum, the majority of BAs are reabsorbed by multiple protein complexes, such as ileal bile acid-binding protein (Ibabp) and apical sodium-dependent bile acid transporter (ASBT) into enterocytes [ 23 ]. This is followed by their secretion into the portal circulation via the basolateral BA transporters organic solute transporter subunit- α (OST- α ), OST- β , and multidrug resistance-associated protein 2 (MRP2).…”

“…The underlined procedures consist of the whole enterohepatic circulation of BA [ 18 , 24 ]. BA de novo synthesis in the liver depends on the regulatory factors such as FXR and its downstream targets in the ileum and liver [ 23 , 25 ]. The whole circulation of BAs effectively emulsifies and drives the fat-soluble vitamins or lipid absorption in the intestine [ 26 , 27 ].…”