Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology

Fuchs, Claudia; Trauner, Michael

doi:10.1038/s41575-021-00566-7

Cited by 205 publications

(153 citation statements)

References 297 publications

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“…Two pathways, the intestinal FXR-FGF19/15 signaling and hepatic FXR-SHP signaling pathways, reportedly contribute to the regulation of hepatic CYP7A1mediated BA synthesis [1][2][3] . Although ingestion of either whey protein isolate or conglycinin upregulated hepatic FXR and SHP expression, ingestion of whey protein isolate and -conglycinin exerted opposite effects on hepatic CYP7A1 expression and BA synthesis in relation to alterations in the intestinal FGF15 expression, plasma FGF15 levels, and hepatic gluconeogenesis.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Bile acids (BAs) are nutrient sensors implicated to act as metabolic regulators that activate BA receptors, such as Farnesoid X receptor (FXR) and Takeda G proteincoupled Receptor 5 (TGR5), in the intestine [1][2][3] . Activation of intestinal FXR, a BAactivated nuclear receptor, produces fibroblast growth factor 19 (FGF19) and its mouse ortholog FGF15, mainly in the enterocytes of the ileum [1][2][3] . FGF19/15 is subsequently secreted into the portal vein and circulated to the liver, where it attenuates hepatic BA synthesis by suppressing the key enzyme cholesterol-7α hydroxylase (CYP7A1) and promotes gallbladder filling [1][2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

“…Activation of intestinal FXR, a BAactivated nuclear receptor, produces fibroblast growth factor 19 (FGF19) and its mouse ortholog FGF15, mainly in the enterocytes of the ileum [1][2][3] . FGF19/15 is subsequently secreted into the portal vein and circulated to the liver, where it attenuates hepatic BA synthesis by suppressing the key enzyme cholesterol-7α hydroxylase (CYP7A1) and promotes gallbladder filling [1][2][3][4] . FGF15/19 is also suggested to act as a metabolic regulator 5 .…”

Section: Introductionmentioning

confidence: 99%

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Ingestion of whey protein and beta-conglycinin exerts opposite effects on intestinal FGF15-mediated hepatic bile acid synthesis in mice.

Nonogaki

Kaji

2022

Preprint

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Farnesoid X receptor (FXR), a BA receptor, and fibroblast growth factor 15 (FGF15) regulate enterohepatic circulation of BAs, glucose, and lipid metabolism. Here we show that ingestion of whey protein isolate, a milk protein, significantly increased plasma FGF15 levels and the expression of FXR and FGF15 in mouse ileum. In addition, ingestion of whey protein isolate significantly suppressed the expression of hepatic cholesterol-7α hydroxylase (CYP7A1), which induces BA synthesis, and decreased the primary BAs, including cholic acid, taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid in the liver compared with controls. Moreover, ingestion of whey protein isolate significantly decreased the expression of Takeda G protein-coupled Receptor 5 (TGR5), glucagon-like peptide 1 (GLP-1), and tryptophan hydroxylase1 (Tph1) in the small intestine, and plasma serotonin and insulin levels. On the other hand, ingestion of the soy protein β-conglycinin significantly decreased the expression of FGF15 in the ileum and plasma FGF15 levels, leading to increased expression of hepatic CYP7A1 and BA synthesis. Moreover, ingestion of β-conglycinin significantly increased the expression of intestinal TGR5, GLP-1, and Tph1, and plasma 5-HT and insulin levels. These findings suggest that whey protein and β-conglycinin have opposite effects on intestinal FGF15-mediated hepatic BA synthesis and intestinal serotonin secretion in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ingestion of whey protein and beta-conglycinin exerts opposite effects on intestinal FGF15-mediated hepatic bile acid synthesis in mice.

Nonogaki

Kaji

2022

Preprint

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“…In the classic pathway, the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1) is mainly responsible for the cholic acid (CA) and CDCA synthesis. As far as the alternative pathway, the main rate-limiting enzyme is sterol 27-hydrolase (CYP27A1), which responds to CDCA production ( Fuchs and Trauner, 2022 ). It is reported that extracts from some natural products can promote LCA production via activating intestinal farnesoid X receptor (FXR) signaling and increasing the gene expression of BA alternative pathway synthetases CYP7B1 and CYP27A1 ( Wu et al, 2021 ).…”

Section: The Synthesis Of Lcamentioning

confidence: 99%

The Effect of Lithocholic Acid on the Gut-Liver Axis

Sheng

Zhang

2022

Front. Pharmacol.

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Lithocholic acid (LCA) is a monohydroxy bile acid produced by intestinal flora, which has been found to be associated with a variety of hepatic and intestinal diseases. LCA is previously considered to be toxic, however, recent studies revealed that LCA and its derivatives may exert anti-inflammatory and anti-tumor effects under certain conditions. LCA goes through enterohepatic circulation along with other bile acids, here, we mainly discuss the effects of LCA on the gut-liver axis, including the regulation of gut microbiota, intestinal barrier, and relevant nuclear receptors (VDR, PXR) and G protein-coupled receptor five in related diseases. In addition, we also find that some natural ingredients are involved in regulating the detoxification and excretion of LCA, and the interaction with LCA also mediates its own biological activity.

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Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid

Wu,

Liu,

Xia

et al. 2023

Advanced Science

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Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5−/−) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re‐expression of hepatic SLC27A5 by an adeno‐associated virus or the reduction of CA levels in the liver using A4250, an apical sodium‐dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5−/− mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA‐induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

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Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology

Cited by 205 publications

References 297 publications

Ingestion of whey protein and beta-conglycinin exerts opposite effects on intestinal FGF15-mediated hepatic bile acid synthesis in mice.

Ingestion of whey protein and beta-conglycinin exerts opposite effects on intestinal FGF15-mediated hepatic bile acid synthesis in mice.

The Effect of Lithocholic Acid on the Gut-Liver Axis

Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid

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