scholarly journals Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators

2017 ◽  
Vol 312 (1) ◽  
pp. H21-H32 ◽  
Author(s):  
Stefano Fiorucci ◽  
Angela Zampella ◽  
Giuseppe Cirino ◽  
Mariarosaria Bucci ◽  
Eleonora Distrutti
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Vascular System ◽  
Cholesterol Metabolism ◽  
Lithocholic Acid ◽  
Secondary Bile Acid ◽  
Complex Disorders ◽  
Specific Effects ◽  
Symbiotic Relation ◽  
Species Specific

Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X-receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium-activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension.

Pharmacological effects of secondary bile acid microparticles in diabetic murine model

2020 ◽  
Vol 16 ◽  
Author(s):  
Armin Mooranian ◽  
Nassim Zamani ◽  
Bozica Kovacevic ◽  
Corina Mihaela Ionescu ◽  
Giuseppe Luna ◽  
...  
Keyword(s):  
Bile Acid ◽  
Blood Glucose ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Diabetes Treatment ◽  
Secondary Bile Acid ◽  
Glucose Levels ◽  
Anti Inflammatory ◽  
Antidiabetic Effects

Aim: Examine bile acids effects in Type 2 diabetes. Background: In recent studies, the bile acid ursodeoxycholic acid (UDCA) has shown potent anti-inflammatory effects in obese patients while in type 2 diabetics (T2D) levels of the pro-inflammatory bile acid lithocholic acid were increased, and levels of the anti-inflammatory bile acid chenodeoxycholic acid were decreased, in plasma. Objective: Hence, this study aimed to examine applications of novel UDCA nanoparticles in diabetes. Methods: Diabetic balb/c adult mice were divided into three equal groups and gavaged daily with either empty microcapsules, free UDCA, or microencapsulated UDCA over two weeks. Their blood, tissues, urine, and faeces were collected for blood glucose, inflammation, and bile acid analyses. UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Results: UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Conclusion: Bile acids modulated the bile profile without affecting blood glucose levels.

scholarly journals Human gut bacteria produce TH17-modulating bile acid metabolites

2021 ◽  
Author(s):  
Donggi Paik ◽  
Lina Yao ◽  
Yancong Zhang ◽  
Sena Bae ◽  
Gabriel D. D'Agostino ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Retinoic Acid Receptor ◽  
Gut Bacteria ◽  
Orphan Nuclear Receptor ◽  
Human Gut ◽  
Secondary Bile Acid ◽  
Bowel Diseases ◽  
And Function

The microbiota plays a pivotal role in gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17a (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation. While it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown. Furthermore, it was not clear whether 3-oxoLCA and other immunomodulatory bile acids are associated with gut inflammatory pathologies in humans. Using a high-throughput screen, we identified human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Like 3-oxoLCA, isoLCA suppressed TH17 differentiation by inhibiting RORγt (retinoic acid receptor-related orphan nuclear receptor γt), a key TH17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase (3α-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). Moreover, levels of these bile acids were inversely correlated with expression of TH17 cell-associated genes. Overall, our data suggest that bacterially produced TH17 cell-inhibitory bile acids may reduce the risk of autoimmune and inflammatory disorders such as IBD.

Identification of unique bile acid-metabolizing bacteria from the microbiome of centenarians

2020 ◽  
Author(s):  
Kenya Honda ◽  
Yuko Sato ◽  
Koji Atarashi ◽  
Damian Plichta ◽  
Yasumichi Arai ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Multidrug Resistant ◽  
Bile Acid Metabolism ◽  
Critical Determinant ◽  
Secondary Bile Acid ◽  
Clostridioides Difficile ◽  
Vancomycin Resistant ◽  
Secondary Bile Acids

Abstract Centenarians, or individuals who have lived more than a century, represent the ultimate model of successful longevity associated with decreased susceptibility to ageing-associated illness and chronic inflammation. The gut microbiota is considered to be a critical determinant of human health and longevity. Here we show that centenarians (average 107 yo) have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids, including iso-, 3-oxo-, and isoallo-lithocholic acid (LCA), as compared to elderly (85-89 yo) and young (21-55 yo) controls. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian’s faecal microbiota, we identified Parabacteroides merdae and Odoribacteraceae strains as effective producers of isoalloLCA. Furthermore, we generated and tested mutant strains of P. merdae to show that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production. This secondary bile acid derivative exerted the most potent antimicrobial effects among the tested bile acid compounds against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and vancomycin-resistant Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to longevity.

scholarly journals The lithocholic acid 6β-hydroxylase cytochrome P-450, CYP 3A10, is an active catalyst of steroid-hormone 6β-hydroxylation

1993 ◽  
Vol 291 (2) ◽  
pp. 429-433 ◽  
Author(s):  
T K H Chang ◽  
J Teixeira ◽  
G Gil ◽  
D J Waxman
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Steroid Hormones ◽  
Lithocholic Acid ◽  
Liver Microsomes ◽  
Microsomal Protein ◽  
Secondary Bile Acid ◽  
Cos Cells ◽  
Major Activity ◽  
Cytochrome P 450

CYP 3A10 is a hamster liver cytochrome P-450 (P450) that encodes lithocholic acid 6 beta-hydroxylase, an enzyme that plays an important role in the detoxification of the cholestatic secondary bile acid lithocholate. Western-blot analysis revealed that the expression of CYP 3A10 protein is male-specific in hamster liver microsomes, a finding that is consistent with earlier analysis of CYP 3A10 mRNA. Since it has not been established whether the specificities of bile acid hydroxylase P450s, such as CYP 3A10, are restricted to their anionic bile acid substrates, we investigated the role of CYP 3A10 in the metabolism of a series of neutral steroid hormones using cDNA directed-expression in COS cells. The steroid hormones examined, testosterone, androstenedione and progesterone, were each metabolized by the expressed CYP 3A10, with 6 beta-hydroxylation corresponding to a major activity in all three instances. CYP 3A10-dependent steroid hydroxylation was increased substantially when the microsomes were prepared from COS cells co-transfected with NADPH:P450 reductase cDNA. In this case, the expressed P450 actively catalysed the 6 beta-hydroxylation of testosterone (288 +/- 23 pmol of product formed/min per mg of COS-cell microsomal protein), androstenedione (107 +/- 19 pmol/min per mg) and progesterone (150 +/- 7 pmol/min per mg). Other major CYP 3A10-mediated steroid hydroxylase activities included androstenedione 16 alpha-hydroxylation, progesterone 16 alpha- and 21-hydroxylation, and the formation of several unidentified products. CYP 3A10 exhibited similar Vmax. values for the 6 beta-hydroxylation of androstenedione and lithocholic acid (132 and 164 pmol/min per mg respectively), but metabolized the bile acid with a 3-fold lower Km (25 microM, as against 75 microM for androstenedione). Together, these studies establish that the substrate specificity of the bile acid hydroxylase CYP 3A10 is not restricted to bile acids, and further suggest that CYP 3A10 can play a physiologically important role in the metabolism of two classes of endogenous P450 substrates:steroid hormones and bile acids.

scholarly journals Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Peipei Li ◽  
Bryan A. Killinger ◽  
Elizabeth Ensink ◽  
Ian Beddows ◽  
Ali Yilmaz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Secondary Bile Acid

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.

Modulatory Nano/Micro Effects of Diabetes Development on Pharmacology of Primary and Secondary Bile Acids Concentrations

2020 ◽  
Vol 16 (8) ◽  
pp. 900-909
Author(s):  
Armin Mooranian ◽  
Nassim Zamani ◽  
Ryu Takechi ◽  
Giuseppe Luna ◽  
Momir Mikov ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Secondary Bile Acid ◽  
Feedback Mechanisms ◽  
Diabetes Development ◽  
Bile Acid Profiles ◽  
Secondary Bile Acids

Background: Recent studies have suggested that hyperglycaemia influences the bile acid profile and concentrations of secondary bile acids in the gut. Introduction: This study aimed to measure changes in the bile acid profile in the gut, tissues, and faeces in type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). Method: T1D and T2D were established in a mouse model. Twenty-one seven-weeks old balb/c mice were randomly divided into three equal groups, healthy, T1D and T2D. Blood, tissue, urine and faeces samples were collected for bile acid measurements. Results: Compared with healthy mice, T1D and T2D mice showed lower levels of the primary bile acid, chenodeoxycholic acid, in the plasma, intestine, and brain, and higher levels of the secondary bile acid, lithocholic acid, in the plasma and pancreas. Levels of the bile acid ursodeoxycholic acid were undetected in healthy mice but were found to be elevated in T1D and T2D mice. Conclusion: Bile acid profiles in other organs were variably influenced by T1D and T2D development, which suggests similarity in effects of T1D and T2D on the bile acid profile, but these effects were not always consistent among all organs, possibly since feedback mechanisms controlling enterohepatic recirculation and bile acid profiles and biotransformation are different in T1D and T2D.

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 Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

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.

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