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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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7368063 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Wang Yifeng Y Gunewardena Sumedha S Li Feng F Matye David J DJ Chen Cheng C Chao Xiaojuan X Jung Taeyoon T Zhang Yuxia Y Czerwiński Maciej M Ni Hong-Min HM Ding Wen-Xing WX Li Tiangang T

Nature communications 20200717 1

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 fi ...[more]

PMID: 32681035

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Project description:We reported previously that mice overexpressing cytochrome P450 7a1 (Cyp7a1; Cyp7a1-tg mice) are protected against high fat diet-induced hypercholesterolemia, obesity, and insulin resistance. Here, we investigated the underlying mechanism of bile acid signaling in maintaining cholesterol homeostasis in Cyp7a1-tg mice. Cyp7a1-tg mice had two-fold higher Cyp7a1 activity and bile acid pool than did wild-type mice. Gallbladder bile acid composition changed from predominantly cholic acid (57%) in wild-type to chenodeoxycholic acid (54%) in Cyp7a1-tg mice. Cyp7a1-tg mice had higher biliary and fecal cholesterol and bile acid secretion rates than did wild-type mice. Surprisingly, hepatic de novo cholesterol synthesis was markedly induced in Cyp7a1-tg mice but intestine fractional cholesterol absorption in Cyp7a1-tg mice remained the same as wild-type mice despite the presence of increased intestine bile acids. Interestingly, hepatic but not intestinal expression of several cholesterol (adenosine triphosphate-binding cassette G5/G8 [ABCG5/G8], scavenger receptor class B, member 1) and bile acid (ABCB11) transporters were significantly induced in Cyp7a1-tg mice. Treatment of mouse or human hepatocytes with a farnesoid X receptor (FXR) agonist GW4064 or bile acids induced hepatic Abcg5/g8 expression. A functional FXR binding site was identified in the Abcg5 gene promoter. Study of tissue-specific Fxr knockout mice demonstrated that loss of the Fxr gene in the liver attenuated bile acid induction of hepatic Abcg5/g8 and gallbladder cholesterol content, suggesting a role of FXR in the regulation of cholesterol transport.This study revealed a new mechanism by which increased Cyp7a1 activity expands the hydrophobic bile acid pool, stimulating hepatic cholesterol synthesis and biliary cholesterol secretion without increasing intestinal cholesterol absorption. This study demonstrated that Cyp7a1 plays a critical role in maintaining cholesterol homeostasis and underscores the importance of bile acid signaling in regulating overall cholesterol homeostasis.

Project description:Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute significantly to control of hepatic bile acid synthesis. However, scientific evidence supporting this assumption is primarily based on gene expression data. Using intestine-selective FXR knockout mice (iFXR-KO), we show that contribution of intestinal FXR-Fgf15 signalling in regulation of hepatic cholesterol 7?-hydroxylase (Cyp7A1) expression depends on time of the day with increased hepatic Cyp7A1 expression in iFXR-KO mice compared with controls exclusively during the dark phase. To assess the physiological relevance hereof, we determined effects of intestine-selective deletion of FXR on physiological parameters such as bile formation and kinetics of the enterohepatic circulation of bile acids. It appeared that intestinal FXR deficiency leads to a modest but significant increase in cholic acid pool size, without changes in fractional turnover rate. As a consequence, bile flow and biliary bile acid secretion rates were increased in iFXR-KO mice compared with controls. Feeding a bile acid-containing diet or treatment with a bile acid sequestrant similarly affected bile formation in iFXR-KO and control mice and induced similar changes in Cyp7A1 and Cyp8B1 expression patterns. In conclusion, this study is the first to demonstrate the physiological relevance of the contribution of the intestinal FXR-Fgf15 signalling pathway in control of hepatic bile acid synthesis. Fgf15 contributes to the regulation of hepatic bile acid synthesis in mice mainly during the dark phase. Expansion of the circulating bile acid pool as well as bile acid sequestration diminishes the contribution of intestinal FXR-Fgf15 signalling in control of hepatic bile acid synthesis and bile formation.

Project description:Rationale: An improved understanding of thyroid hormone (TH) action on cholesterol metabolism will facilitate the identification of novel therapeutic targets for hypercholesterolemia. TH-regulated microRNAs (miRNAs) have been implicated in TH-controlled biological processes; however, whether and how TH-regulated miRNAs mediate the cholesterol-lowering effect of TH remains unclear. Our aim was to identify TH-regulated microRNAs that have cholesterol-lowering effects and explore the underlying mechanism. Method: Microarray and RNA-seq were performed to identify TH-regulated microRNAs and the genes regulated by mmu-miR-378-3p (miR-378) in the liver of mice, respectively. Recombinant adenoviruses encoding miR-378, Mafg, and shRNA for Mafg, antagomiR-378, liver-specific miR-378 transgenic mice, and miR-378 knockout mice were employed to investigate the roles of hepatic miR-378 and MAFG in cholesterol and bile acid homeostasis. The levels of bile salt species were determined by using UFLC-Triple-time of flight/MS. Results: Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces serum cholesterol levels, accompanied with an increase in the expression of key enzymes in primary bile acid synthetic pathways and corresponding increases in biliary and fecal bile acid levels. Consistently, liver-specific miR-378 transgenic mice with moderate overexpression of hepatic miR-378 display decreased serum cholesterol levels and resistance to diet-induced hypercholesterolemia, while mice lacking miR-378 exhibit defects in bile acid and cholesterol homeostasis. Mechanistically, hepatic miR-378 regulates the expression of key enzymes in both classic and alternative bile acid synthetic pathways through MAFG, a transcriptional repressor, thereby modulating bile acid and cholesterol metabolism. Conclusions: TH-responsive hepatic miR-378 is capable of modulating serum cholesterol levels by regulating both the classic and alternative BA synthetic pathways. Our study not only identifies a previously undescribed role of hepatic miR-378 but also provides new cholesterol-lowering approaches.

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

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

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