Bile Acid Synthetic Defects and Liver Disease

2000 ◽  
Vol 3 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Kevin E. Bove ◽  
Cynthia C. Daugherty ◽  
Wes Tyson ◽  
Gary Mierau ◽  
James E. Heubi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid

scholarly journals Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

2021 ◽  
Author(s):  
Richard Radun ◽  
Michael Trauner
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Therapeutic Potential ◽  
Farnesoid X Receptor ◽  
Metabolic Homeostasis ◽  
Nonalcoholic Fatty Liver ◽  
Metabolic Dysregulation ◽  
Attractive Therapeutic Target

AbstractNonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.

Bile acid conjugation in early stage cholestatic liver disease before and during treatment with ursodeoxycholic acid

1996 ◽  
Vol 248 (2) ◽  
pp. 175-185 ◽  
Author(s):  
Mario Fracchia ◽  
Kenneth D.R. Setchell ◽  
Andrea Crosignani ◽  
Mauro Podda ◽  
Nancy O'Connell ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Early Stage ◽  
Cholestatic Liver Disease

Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet

2005 ◽  
Vol 289 (2) ◽  
pp. G300-G307 ◽  
Author(s):  
Robert P. Erickson ◽  
Achyut Bhattacharyya ◽  
Robert J. Hunter ◽  
Randall A. Heidenreich ◽  
Nathan J. Cherrington
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
Cholestatic Hepatitis ◽  
Diffuse Fibrosis ◽  
Acid Transport ◽  
High Fat ◽  
Bile Acid Transport ◽  
Niemann Pick

Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1−/− mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol (“high-fat”) diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1–5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1−/− mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1−/− mice on the high-fat diet; it was massively increased in the Ldlr−/− mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. γ-Glutamyltransferase was also elevated in Npc1−/− mice, more so on the high-fat diet. Mrps 1–5 were elevated in Npc1−/− liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1−/− liver and were suppressed by the high-fat diet. In conclusion, Npc1−/− mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.

scholarly journals Disease-Associated Gut Microbiota Reduces the Profile of Secondary Bile Acids in Pediatric Nonalcoholic Fatty Liver Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiake Yu ◽  
Hu Zhang ◽  
Liya Chen ◽  
Yufei Ruan ◽  
Yiping Chen ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Bile Acids ◽  
Fatty Liver Disease ◽  
Healthy Children ◽  
Nonalcoholic Fatty Liver ◽  
Secondary Bile Acids

Children with nonalcoholic fatty liver disease (NAFLD) display an altered gut microbiota compared with healthy children. However, little is known about the fecal bile acid profiles and their association with gut microbiota dysbiosis in pediatric NAFLD. A total of 68 children were enrolled in this study, including 32 NAFLD patients and 36 healthy children. Fecal samples were collected and analyzed by metagenomic sequencing to determine the changes in the gut microbiota of children with NAFLD, and an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system was used to quantify the concentrations of primary and secondary bile acids. The associations between the gut microbiota and concentrations of primary and secondary bile acids in the fecal samples were then analyzed. We found that children with NAFLD exhibited reduced levels of secondary bile acids and alterations in bile acid biotransforming-related bacteria in the feces. Notably, the decrease in Eubacterium and Ruminococcaceae bacteria, which express bile salt hydrolase and 7α-dehydroxylase, was significantly positively correlated with the level of fecal lithocholic acid (LCA). However, the level of fecal LCA was negatively associated with the abundance of the potential pathogen Escherichia coli that was enriched in children with NAFLD. Pediatric NAFLD is characterized by an altered profile of gut microbiota and fecal bile acids. This study demonstrates that the disease-associated gut microbiota is linked with decreased concentrations of secondary bile acids in the feces. The disease-associated gut microbiota likely inhibits the conversion of primary to secondary bile acids.

scholarly journals Role of Bile Acids in Dysbiosis and Treatment of Nonalcoholic Fatty Liver Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Caihua Wang ◽  
Chunpeng Zhu ◽  
Liming Shao ◽  
Jun Ye ◽  
Yimin Shen ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Bile Acids ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Bile Acid Receptors

Nonalcoholic fatty liver disease (NAFLD) is a major health threat around the world and is characterized by dysbiosis. Primary bile acids are synthesized in the liver and converted into secondary bile acids by gut microbiota. Recent studies support the role of bile acids in modulating dysbiosis and NAFLD, while the mechanisms are not well elucidated. Dysbiosis may alter the size and the composition of the bile acid pool, resulting in reduced signaling of bile acid receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). These receptors are essential in lipid and glucose metabolism, and impaired bile acid signaling may cause NAFLD. Bile acids also reciprocally regulate the gut microbiota directly via antibacterial activity and indirectly via FXR. Therefore, bile acid signaling is closely linked to dysbiosis and NAFLD. During the past decade, stimulation of bile acid receptors with their agonists has been extensively explored for the treatment of NAFLD in both animal models and clinical trials. Early evidence has suggested the potential of bile acid receptor agonists in NAFLD management, but their long-term safety and effectiveness need further clarification.

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