Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

Kunst, Roni F.; Verkade, Henkjan J.; Elferink, Ronald P.J. Oude; Graaf, Stan F.J. van de

doi:10.1002/hep.31651

Cited by 30 publications

(31 citation statements)

References 67 publications

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“…Bile acids can be reabsorbed in the small intestine in a variety of ways. The distal ileum is the main site for bile acid reabsorption because the apical sodium-dependent bile acid transporter (ASBT) is mainly expressed here ( 53 ). Out et al found that ASBT-dependent ileal bile acid reabsorption was inhibited in intestinal Gata4 specific knockout mice, which is related to changes in gut microbiota in an ASBT-dependent pathway through Gata4 ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

NMN Maintains Intestinal Homeostasis by Regulating the Gut Microbiota

et al. 2021

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The aim of this study was to determine the effects of long-term Nicotinamide mononucleotide (NMN) treatment on modulating gut microbiota diversity and composition, as well as its association with intestinal barrier function. In this study, C57BL/6J mice were fed different concentrations of NMN, and their feces were collected for detection of 16S rDNA and non-targeted metabolites to explore the effects of NMN on intestinal microbiota and metabolites. The results revealed that NMN increased the abundance of butyric acid-producing bacteria (Ruminococcae_UCG-014 and Prevotellaceae_NK3B31_group) and other probiotics (Akkermansia muciniphila), while the abundance of several harmful bacteria (Bilophila and Oscillibacter) were decreased after NMN treatment. Meanwhile, the level of bile acid-related metabolites in feces from the G1 group (0.1 mg/ml) was significantly increased compared to the control group, including cholic acid, taurodeoxycholic acid, taurocholic acid, glycocholic acid, and tauro-β-muricholic acid. In addition, long-term NMN treatment affected the permeability of the intestinal mucosa. The number of goblet cells and mucus thickness increased, as well as expression of tight junction protein. These results demonstrate that NMN reduced intestinal mucosal permeability and exerts a protective effect on the intestinal tract. This study lays the foundation for exploring NMN's utility in clinical research.

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Section: Discussionmentioning

confidence: 99%

NMN Maintains Intestinal Homeostasis by Regulating the Gut Microbiota

et al. 2021

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“…Uptake and efflux of BAs are mediated by a series of efficient BA transporters in the liver. Sodium taurocholate cotransporting polypeptide ( Ntcp ) and organic anion-transporting polypeptides ( Oatps ) are responsible for transporting BAs from portal blood into hepatocytes ( Kunst et al, 2020 ). mRNA expression of Oatp1a1 and Oatp1a4 was decreased significantly and increased in mice fed the LD, respectively, whereas APS reversed these changes ( Supplementary Figure S3A ).…”

Section: Resultsmentioning

confidence: 99%

“…For sinusoidal uptake transporters, increased mRNA expression of Mrp3 and Mrp4 in the LD group was decreased significantly by APS supplementation ( Supplementary Figure S3A ). Bsep and Mrp2 pump bile salts out of hepatocytes into primary bile ( Kunst et al, 2020 ). mRNA expression of Bsep was increased significantly in mice fed the LD, but APS had little effect on mRNA expression of Bsep and Mrp2 ( Supplementary Figure S3A ).…”

Section: Resultsmentioning

confidence: 99%

“…Cholesterol is secreted by the adenosine triphosphate-binding cassette ( Abc ) transporters Abcg5 and Abcg8 ( Lammert et al, 2016 ). BA secretion is mediated by bile acid export pump ( Bsep ) and multidrug resistance protein ( Mrp ) 2 ( Kunst et al, 2020 ). Abcb4 (also known as multidrug resistance protein 3) is a major transporter of phospholipids ( Poupon et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Astragalus Polysaccharides Ameliorate Diet-Induced Gallstone Formation by Modulating Synthesis of Bile Acids and the Gut Microbiota

Zhuang

Shen

et al. 2021

Front. Pharmacol.

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Cholesterol gallstone (CG) disease has relationships with several metabolic abnormalities. Astragalus polysaccharides (APS) have been shown to have multiple benefits against metabolic disorders. We attempted to uncover the effect and mechanism of action of APS on diet-induced CG formation in mice. Animals were fed a chow diet or lithogenic diet (LD) with or without APS supplementation. The effect of APS on CG formation was evaluated. The level of individual bile acids (BAs) in gallbladder bile and ileum were measured by liquid chromatography-tandem mass spectrometry. Real-time reverse transcription-quantitative polymerase chain reaction and western blotting were used to assess expression of the genes involved in BA metabolism and the enterohepatic circulation. Cecal contents were collected to characterize microbiota profiles. APS ameliorated LD-induced CG formation in mice. APS reduced the level of total cholesterol, bile acid hydrophobicity index and cholesterol saturation index in gallbladder bile. The protective effect of APS might result from reduced absorption of cholic acid in the intestine and increased hepatic BA synthesis. APS relieved the LD-induced activation of the intestinal farnesoid X receptor and decreased ileal expression of fibroblast growth factor 15. In the liver, expression of cytochrome P450 (Cyp) enzyme Cyp7a1 and Cyp7b1 was increased, whereas expression of adenosine triphosphate-binding cassette (Abc) transporters Abcg5 and Abcg8 was decreased by APS. APS improved the diversity of the gut microbiota and increased the relative abundance of the Bacteroidetes phylum. APS had demonstratable benefits against CG disease, which might be associated with enhanced BA synthesis and improved gut microbiota. Our results suggest that APS may be a potential strategy for the prevention of CG disease.

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“…The bile acids then travel via the portal vein back to the liver, where they are taken up from the sinusoids into the hepatocytes via SLC10A1 (or basolateral sodium taurocholate cotransporting polypeptide (NTCP)) transporter [ 4 , 5 ], thereby completing the enterohepatic circulation [ 6 ]. Importantly, the polarized distribution of apical and basolateral bile acid transporters in the hepatocytes and enterocytes thus is necessary for the enterohepatic circulation of bile acids [ 7 ] ( Figure 1 ).…”

Section: An Introduction To the Enterohepatic Circulation Of Bile mentioning

confidence: 99%

A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators

Li¹,

Sun²,

IJzendoorn³

2021

Biology

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Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1F4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.

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Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

Cited by 30 publications

References 67 publications

NMN Maintains Intestinal Homeostasis by Regulating the Gut Microbiota

NMN Maintains Intestinal Homeostasis by Regulating the Gut Microbiota

Astragalus Polysaccharides Ameliorate Diet-Induced Gallstone Formation by Modulating Synthesis of Bile Acids and the Gut Microbiota

A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators

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