Browsing by Subject "Bile acids"

Now showing 1 - 6 of 6
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    Bile Acids in Autoimmune Liver Disease: Unveiling the Nexus of Inflammation, Inflammatory Cells, and Treatment Strategies
    (MDPI, 2023-11-29) Zhou, Tianhao; Ismail, AbdiGhani; Francis, Heather; Medicine, School of Medicine
    As bile acids not solely play an essential role in nutrition absorption, but also in regulating metabolic functions as well as immune response, bile acids and their signaling pathways are increasingly acknowledged as potential therapeutic targets in the context of chronic liver diseases. Bile acid receptors such as G protein bile acid-activated receptor 1 and farnesoid X receptor are expressed in different immune cells engaged in innate immunity. Recently, a series of studies have revealed distinct functions of bile acids and bile acid receptors within the adaptive immune system. In addition, a variety of molecules targeting bile acid receptors and transporters are currently in advanced stages of clinical development. Autoimmune liver diseases including conditions like primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis can lead to chronic inflammation, fibrosis, and even cirrhosis and liver failure. In this review, we focus on the role of bile acids in the inflammatory aspects of autoimmune liver diseases.
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    Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis
    (Elsevier, 2024) Ceci, Ludovica; Gaudio, Eugenio; Kennedy, Lindsey; Medicine, School of Medicine
    Biliary fibrosis is seen in cholangiopathies, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In PBC and PSC, biliary fibrosis is associated with worse outcomes and histologic scores. Within the liver, both hepatic stellate cells (HSCs) and portal fibroblasts (PFs) contribute to biliary fibrosis, but their roles can differ. PFs reside near the bile ducts and may be the first responders to biliary damage, whereas HSCs may be recruited later and initiate bridging fibrosis. Indeed, different models of biliary fibrosis can activate PFs and HSCs to varying degrees. The portal niche can be composed of cholangiocytes, HSCs, PFs, endothelial cells, and various immune cells, and interactions between these cell types drive biliary fibrosis. In this review, we discuss the mechanisms of biliary fibrosis and the roles of PFs and HSCs in this process. We will also evaluate cellular interactions and mechanisms that contribute to biliary fibrosis in different models and highlight future perspectives and potential therapeutics.
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    Dual Role of Bile Acids on the Biliary Epithelium: Friend or Foe?
    (MDPI, 2019-04-16) Baiocchi, Leonardo; Zhou, Tianhao; Liangpunsakul, Suthat; Lenci, Ilaria; Santopaolo, Francesco; Meng, Fanyin; Kennedy, Lindsey; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
    Bile acids are a family of amphipathic compounds predominantly known for their role in solubilizing and absorbing hydrophobic compounds (including liposoluble vitamins) in the intestine. Bile acids also are key signaling molecules and inflammatory agents that activate transcriptional factors and cell signaling pathways that regulate lipid, glucose, and energy metabolism in various human disorders, including chronic liver diseases. However, in the last decade increased awareness has been founded on the physiological and chemical heterogeneity of this category of compounds and their possible beneficial or injurious effects on the biliary tree. In this review, we provide an update on the current understanding of the molecular mechanism involving bile acid and biliary epithelium. The last achievements of the research in this field are summarized, focusing on the molecular aspects and the elements with relevance regarding human liver diseases.
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    Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease
    (MDPI, 2021-08-12) Zhou, Tianhao; Kundu, Debjyoti; Robles-Linares, Jonathan; Meadows, Vik; Sato, Keisaku; Baiocchi, Leonardo; Ekser, Burcin; Glaser, Shannon; Alpini, Gianfranco; Francis, Heather; Kennedy, Lindsey; Medicine, School of Medicine
    Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.
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    Loss of apical sodium bile acid transporter alters bile acid circulation and reduces biliary damage in cholangitis
    (American Physiological Society, 2023) Meadows, Vik; Marakovits, Corinn; Ekser, Burcin; Kundu, Debjyoti; Zhou, Tianhao; Kyritsi, Konstantina; Pham, Linh; Chen, Lixian; Kennedy, Lindsey; Ceci, Ludovica; Wu, Nan; Carpino, Guido; Zhang, Wenjun; Isidan, Abdulkadir; Meyer, Alison; Owen, Travis; Gaudio, Eugenio; Onori, Paolo; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Primary sclerosing cholangitis (PSC) is characterized by increased ductular reaction (DR), liver fibrosis, hepatic total bile acid (TBA) levels, and mast cell (MC) infiltration. Apical sodium BA transporter (ASBT) expression increases in cholestasis, and ileal inhibition reduces PSC phenotypes. FVB/NJ and multidrug-resistant 2 knockout (Mdr2-/-) mice were treated with control or ASBT Vivo-Morpholino (VM). We measured 1) ASBT expression and MC presence in liver/ileum; 2) liver damage/DR; 3) hepatic fibrosis/inflammation; 4) biliary inflammation/histamine serum content; and 5) gut barrier integrity/hepatic bacterial translocation. TBA/BA composition was measured in cholangiocyte/hepatocyte supernatants, intestine, liver, serum, and feces. Shotgun analysis was performed to ascertain microbiome changes. In vitro, cholangiocytes were treated with BAs ± ASBT VM, and histamine content and farnesoid X receptor (FXR) signaling were determined. Treated cholangiocytes were cocultured with MCs, and FXR signaling, inflammation, and MC activation were measured. Human patients were evaluated for ASBT/MC expression and histamine/TBA content in bile. Control patient- and PSC patient-derived three-dimensional (3-D) organoids were generated; ASBT, chymase, histamine, and fibroblast growth factor-19 (FGF19) were evaluated. ASBT VM in Mdr2-/- mice decreased 1) biliary ASBT expression, 2) PSC phenotypes, 3) hepatic TBA, and 4) gut barrier integrity compared with control. We found alterations between wild-type (WT) and Mdr2-/- mouse microbiome, and ASBT/MC and bile histamine content increased in cholestatic patients. BA-stimulated cholangiocytes increased MC activation/FXR signaling via ASBT, and human PSC-derived 3-D organoids secrete histamine/FGF19. Inhibition of hepatic ASBT ameliorates cholestatic phenotypes by reducing cholehepatic BA signaling, biliary inflammation, and histamine levels. ASBT regulation of hepatic BA signaling offers a therapeutic avenue for PSC. NEW & NOTEWORTHY: We evaluated knockdown of the apical sodium bile acid transporter (ASBT) using Vivo-Morpholino in Mdr2KO mice. ASBT inhibition decreases primary sclerosing cholangitis (PSC) pathogenesis by reducing hepatic mast cell infiltration, altering bile acid species/cholehepatic shunt, and regulating gut inflammation/dysbiosis. Since a large cohort of PSC patients present with IBD, this study is clinically important. We validated findings in human PSC and PSC-IBD along with studies in novel human 3-D organoids formed from human PSC livers.
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    Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
    (Cell Press, 2020-11-17) Baloni, Priyanka; Funk, Cory C.; Yan, Jingwen; Yurkovich, James T.; Kueider-Paisley, Alexandra; Nho, Kwangsik; Heinken, Almut; Jia, Wei; Mahmoudiandehkordi, Siamak; Louie, Gregory; Saykin, Andrew J.; Arnold, Matthias; Kastenmüller, Gabi; Griffiths, William J.; Thiele, Ines; Kaddurah-Daouk, Rima; Price, Nathan D.; Radiology and Imaging Sciences, School of Medicine
    Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.