Bile formation and secretion: An update

Boyer, James L.; Soroka, Carol J.

doi:10.1016/j.jhep.2021.02.011

Cited by 70 publications

(45 citation statements)

References 101 publications

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“…ABCB1 absorbs and transfers out of the cells the exogenous substances that enter the body and the harmful toxins produced by the body's metabolism. The transporter MDR1 located at the top of the bile capillary is the determinant of bile secretion and composition, and its main function is to transport hydrophobic compounds into the bile (Boyer and Soroka, 2021). In addition, some studies have shown that MDR1 promoted the excretion of bilirubin and bile acid, and accelerated the efflux of hepatotoxic substances, so as to dispel jaundice, cholagogic and detoxification, thereby regulating bile acid metabolism (Tang et al, 2016;Jetter and Kullak-Ublick, 2020).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

et al. 2021

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Background: Paeoniflorin (PF), the major active compound isolated from the roots of Paeonia lactiflora Pall., has been used in the treatment of severe hepatic diseases for several decades and displays bright prospects in liver protective effect. However, its biological mechanism that regulates bile acid metabolism and cholestatic liver injury has not been fully elucidated. Our study aims to investigate the mechanism by which PF in the treatment of cholestatic liver injury using a comprehensive approach combining metabolomics and network pharmacological analysis.Methods: The hepatoprotective effect of PF against cholestasis liver injury, induced by α-naphthylisothiocyanate (ANIT), was evaluated in rats. The serum biochemical indices including ALT, AST, TBA, TBIL, ALP, ALB, and the pathological characteristics of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to explore the feces of rats with ANIT-induced cholestatic liver injury treated with PF and the potential biomarkers were screened by metabolomics. The targets for the regulation of potential biomarkers by PF were screened by network pharmacology, and then the relevant key targets were verified by immunohistochemical and western blotting methods.Results: PF significantly improved serum indexes and alleviated liver histological damage. Metabolomics analyses showed that the therapeutic effect of PF is mainly associated with the regulation of 13 metabolites involved in 16 metabolic pathways. The “PF-targets-metabolites” interaction network was constructed, and then five key targets including CDC25B, CYP2C9, MAOB, mTOR, and ABCB1 that regulated the potential biomarkers were obtained. The above five targets were further verified by immunohistochemistry and western blotting, and the results showed that PF significantly improved the expression of key proteins regulating these biomarkers.Conclusion: Our study provides direct evidence for the modulatory properties of PF treatment on ANIT-induced cholestatic liver injury using metabolomics and network pharmacology analyses. PF exhibits favorable pharmacological effect by regulating related signal pathways and key targets for biomarkers. Therefore, these findings may help better understand the complex mechanisms and provide a new and effective approach to the treatment of cholestatic liver injury.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

et al. 2021

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“…After food ingestion, the gallbladder releases these BAs into the duodenum, where they function in the small intestine and colon. After the BAs assist in the digestion of food, most are reabsorbed back into the liver in a process known as the enterohepatic circulation of BAs ( 45 ). A number of recent studies have found that unabsorbed BAs in the intestine can be used as substrates for microbial metabolism and further transformed into secondary BAs through hydrolase or dehydrogenase enzymes.…”

Section: Gut Microbiota and Metabolitesmentioning

confidence: 99%

“…These intestinal bacteria are mainly composed of Lactobacillus, Streptococcus, Enterobacter, Enterococcus, Clostridium, Lactobacillus, Veronococcus ( 46 ). They separate BAs from glycine or taurine to form mainly deoxycholic acid (DCA) and lithocholic acid (LCA), which in turn, may be further recirculated to the liver and, like primary BAs, combine with glycine or taurine and are excreted in small amounts in the feces ( 45 ).…”

Section: Gut Microbiota and Metabolitesmentioning

confidence: 99%

Gut Microbiota in Adipose Tissue Dysfunction Induced Cardiovascular Disease: Role as a Metabolic Organ

et al. 2021

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The gut microbiome has emerged as a key regulator of host metabolism. Accumulating evidence has indicated that the gut microbiota is involved in the development of various human diseases. This association relies on the structure and metabolites of the gut microbiota. The gut microbiota metabolizes the diet ingested by the host into a series of metabolites, including short chain fatty acids, secondary bile acids, trimethylamine N-oxide, and branched-chain amino acids, which affects the physiological processes of the host by activating numerous signaling pathways. In this review, we first summarize the various mechanisms through which the gut microbiota influences adipose tissue dysfunction and metabolic processes that subsequently cause cardiovascular diseases, highlighting the complex interactions between gut microbes, their metabolites, and the metabolic activity of the host. Furthermore, we investigated the current status of clinical therapies for adipose tissue dysfunction directed at the gut microbiota. Finally, we discuss the challenges that remain to be addressed before this field of research can be translated to everyday clinical practice.

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“…It may also contain exogenous drugs, xenobiotics and environmental toxins [3]. Bile is first secreted by the hepatocyte into the canalicular lumen, where biliary flow is aided by transcellular and paracellular fluid movement as well as peristaltic actin contractions [4]. This bile is then modified by secretory and absorptive processes in the bile duct epithelium as it flows distally through the bile ducts.…”

Section: Normal Bile Secretion and Flowmentioning

confidence: 99%

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

Jeyaraj

Bounford

Ruth

et al. 2021

Genes

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Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.

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Bile formation and secretion: An update

Cited by 70 publications

References 101 publications

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

Gut Microbiota in Adipose Tissue Dysfunction Induced Cardiovascular Disease: Role as a Metabolic Organ

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

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