Dynamics of the enterohepatic circulation of bile acids in healthy humans

2021 ◽  
Author(s):  
Frans Stellaard ◽  
Dieter Lütjohann
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Enterohepatic Circulation ◽  
Feedback Inhibition ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Healthy Humans

Regulation of bile acid metabolism is normally discussed as the regulation of bile acid synthesis, which serves to compensate for intestinal loss in order to maintain a constant pool size. After a meal, bile acids start cycling in the enterohepatic circulation. Farnesoid X receptor-dependent ileal and hepatic processes lead to negative feedback inhibition of bile acid synthesis. When the intestinal bile acid flux decreases, the inhibition of synthesis is released. The degree of inhibition of synthesis and the mechanism and degree of activation are still unknown. Moreover, in humans, a biphasic diurnal expression pattern of bile acid synthesis has been documented, indicating maximal synthesis around 3 pm and 9 pm. Quantitative data on the hourly synthesis schedule as compensation for intestinal loss are lacking. In this review, we describe the classical view on bile acid metabolism and present alternative concepts that are based on the overlooked feature that bile acids transit through the enterohepatic circulation very rapidly. A daily profile of the cycling and total bile acid pool sizes and potential controlled and uncontrolled mechanisms for synthesis are predicted. It remains to be elucidated by which mechanism clock genes interact with the Farnesoid X receptor-controlled regulation of bile acid synthesis. This mechanism could become an attractive target to enhance bile acid synthesis at night, when cholesterol synthesis is high, thus lowering serum LDL-cholesterol.

Abstract 49: The Transcriptional Repressor MafG Regulates Cholesterol Catabolism

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Thomas Q de Aguiar Vallim ◽  
Elizabeth J Tarling ◽  
Hannah Ahn ◽  
Lee R Hagey ◽  
Casey E Romanoski ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Metabolic Diseases ◽  
Cholesterol Metabolism ◽  
Transcriptional Repressor ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Metabolism ◽  
Biliary Bile Acid

Elevated circulating cholesterol levels is a major risk factor for cardiovascular diseases (CVD), and therefore understanding pathways that affect cholesterol metabolism are important for potential treatment of CVD. The major route for cholesterol excretion is through its catabolism to bile acids. Specific bile acids are also potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis ( Cyp7a1 , Cyp8b1 ) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway, and modifies the biliary bile acid composition. In contrast, MafG loss-of-function studies cause de-repression of the bile acid genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-Seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR. The identification of this pathway will likely have important implications in metabolic diseases.

scholarly journals Myostatin Knockout Regulates Bile Acid Metabolism by Promoting Bile Acid Synthesis in Cattle

Animals ◽  
2022 ◽  
Vol 12 (2) ◽  
pp. 205
Author(s):  
Di Wu ◽  
Mingjuan Gu ◽  
Zhuying Wei ◽  
Chunling Bai ◽  
Guanghua Su ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Negative Regulator ◽  
Bile Acid Metabolism ◽  
Metabolomic Analysis ◽  
Metabolomics Data

Myostatin (MSTN) is a major negative regulator of skeletal muscle mass and causes a variety of metabolic changes. However, the effect of MSTN knockout on bile acid metabolism has rarely been reported. In this study, the physiological and biochemical alterations of serum in MSTN+/− and wild type (WT) cattle were investigated. There were no significant changes in liver and kidney biochemical indexes. However, compared with the WT cattle, lactate dehydrogenase, total bile acid (TBA), cholesterol, and high-density lipoprotein (HDL) in the MSTN+/− cattle were significantly increased, and glucose, low-density lipoprotein (LDL), and triglycerides (TG) were significantly decreased, indicating that MSTN knockout affected glucose and lipid metabolism and total bile acids content. Targeted metabolomic analysis of the bile acids and their derivatives was performed on serum samples and found that bile acids were significantly increased in the MSTN+/− cattle compared with the WT cattle. As the only bile acid synthesis organ in the body, we performed metabolomic analysis on the liver to study the effect of MSTN knockout on hepatic metabolism. Metabolic pathway enrichment analysis of differential metabolites showed significant enrichment of the primary bile acid biosynthesis and bile secretion pathway in the MSTN+/− cattle. Targeted metabolomics data further showed that MSTN knockout significantly increased bile acid content in the liver, which may have resulted from enhanced bile acid synthesis due to the expression of bile acid synthesis genes, cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), and upregulation in the liver of the MSTN+/− cattle. These results indicate that MSTN knockout does not adversely affect bovine fitness but regulates bile acid metabolism via enhanced bile acid synthesis. This further suggests a role of MSTN in regulating metabolism.

scholarly journals Manipulating the Microbiome: An Alternative Treatment for Bile Acid Diarrhoea

2021 ◽  
Vol 12 (2) ◽  
pp. 335-353
Author(s):  
Evette B. M. Hillman ◽  
Sjoerd Rijpkema ◽  
Danielle Carson ◽  
Ramesh P. Arasaradnam ◽  
Elizabeth M. H. Wellington ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Gastrointestinal Disease ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Metabolism ◽  
The United Kingdom ◽  
The 1960S ◽  
Irritable Bowel ◽  
The Uk

Bile acid diarrhoea (BAD) is a widespread gastrointestinal disease that is often misdiagnosed as irritable bowel syndrome and is estimated to affect 1% of the United Kingdom (UK) population alone. BAD is associated with excessive bile acid synthesis secondary to a gastrointestinal or idiopathic disorder (also known as primary BAD). Current licensed treatment in the UK has undesirable effects and has been the same since BAD was first discovered in the 1960s. Bacteria are essential in transforming primary bile acids into secondary bile acids. The profile of an individual’s bile acid pool is central in bile acid homeostasis as bile acids regulate their own synthesis. Therefore, microbiome dysbiosis incurred through changes in diet, stress levels and the introduction of antibiotics may contribute to or be the cause of primary BAD. This literature review focuses on primary BAD, providing an overview of bile acid metabolism, the role of the human gut microbiome in BAD and the potential options for therapeutic intervention in primary BAD through manipulation of the microbiome.

scholarly journals Liver Bile Acid Changes in Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7451
Author(s):  
Harpreet Kaur ◽  
Drew Seeger ◽  
Svetlana Golovko ◽  
Mikhail Golovko ◽  
Colin Kelly Combs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

scholarly journals Recent advances in understanding bile acid homeostasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2029 ◽  
Author(s):  
John YL Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Recent Advances ◽  
Bile Acid Pool Size ◽  
Bile Acid Receptor ◽  
Acid Toxicity ◽  
G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

scholarly journals Arbutin Alleviates the Liver Injury of α-Naphthylisothiocyanate-induced Cholestasis Through Farnesoid X Receptor Activation

2021 ◽  
Vol 9 ◽  
Author(s):  
Peijie Wu ◽  
Ling Qiao ◽  
Han Yu ◽  
Hui Ming ◽  
Chao Liu ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Protective Effect ◽  
Bile Acids ◽  
Liver Toxicity ◽  
Enterohepatic Circulation ◽  
Receptor Activation ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Cholestatic Diseases

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

scholarly journals Bile acid diarrhoea: pathophysiology, diagnosis and management

2020 ◽  
pp. flgastro-2020-101436
Author(s):  
Alexia Farrugia ◽  
Ramesh Arasaradnam
Keyword(s):  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Feedback Loops ◽  
Farnesoid X Receptor ◽  
Delay In Diagnosis ◽  
Negative Feedback Loops ◽  
Irritable Bowel ◽  
Fibroblast Growth Factor 19

The actual incidence of bile acid diarrhoea (BAD) is unknown, however, there is increasing evidence that it is misdiagnosed in up to 30% with diarrhoea-predominant patients with irritable bowel syndrome. Besides this, it may also occur following cholecystectomy, infectious diarrhoea and pelvic chemoradiotherapy.BAD may result from either hepatic overproduction of bile acids or their malabsorption in the terminal ileum. It can result in symptoms such as bowel frequency, urgency, nocturnal defecation, excessive flatulence, abdominal pain and incontinence of stool. Bile acid synthesis is regulated by negative feedback loops related to the enterohepatic circulation, which are dependent on the farnesoid X receptor and fibroblast growth factor 19. Interruption of these feedback loops is thought to cause bile acid overproduction leading to BAD. This process may occur idiopathically or following a specific trigger such as cholecystectomy. There may also be an interplay with the gut microbiota, which has been reported to be significantly different in patients with severe BAD.Patients with suspected BAD are investigated in various ways including radionucleotide imaging such as SeHCAT scans (though this is not available worldwide) and blood tests. However, other methods such as bile acid measurement in stool (either spot test or 48 hours samples) and urine tests have been explored. Importantly, delay in diagnosis and treatment of BAD greatly affects patient’s quality of life and may double the overall cost of diagnosis.

scholarly journals Effects of Rhein on Bile Acid Homeostasis in Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Zhong Xian ◽  
Jingzhuo Tian ◽  
Lianmei Wang ◽  
Yushi Zhang ◽  
Jiayin Han ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Edible Plant ◽  
Clinical Dose ◽  
Acid Accumulation ◽  
Liver And Kidney ◽  
Hepatic Transporters

Rhein, the active ingredient of rhubarb, a medicinal and edible plant, is widely used in clinical practice. However, the effects of repeated intake of rhein on liver function and bile acid metabolism are rarely reported. In this work, we investigated the alterations of 14 bile acids and hepatic transporters after rats were administered with rhein for 5 weeks. There was no obvious injury to the liver and kidney, and there were no significant changes in biochemical indicators. However, 1,000 mg/kg rhein increased the liver total bile acid (TBA) levels, especially taurine-conjugated bile acids (t-CBAs), inhibited the expression of farnesoid X receptor (FXR), small heterodimer partner (SHP), and bile salt export pump (BSEP) mRNA, and upregulated the expression of (cholesterol 7α-hydroxylase) CYP7A1 mRNA. Rhein close to the clinical dose (10 mg/kg and 30 mg/kg) reduced the amounts of TBAs, especially unconjugated bile acids (UCBAs), and elevated the expression of FXR and multidrug resistance-associated protein 3 (Mrp3) mRNA. These results denote that rhein is relatively safe to use at a reasonable dose and timing. 30 mg/kg rhein may promote bile acid transport and reduce bile acid accumulation by upregulating the expression of FXR mRNA and Mrp3 mRNA, potentially resulting in the decrease in serum UBCAs.

Sign in / Sign up

Export Citation Format

Share Document