Browsing by Subject "bile acid"

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    Mast Cells Regulate Bile Acid Signaling and Cholestasis via Alteration of Farnesoid X Receptor/Fibroblast Growth Factor 15 Axis in Mice
    (2022-03) Meadows, Victoria E.; Francis, Heather; Alpini, Gianfranco; Dong, X Charlie; Esker, Burcin; Ren, Hongxia
    Primary Sclerosing Cholangitis (PSC) is a rare and slow progressing cholangiopathy characterized by hepatic inflammation, fibrosis and ductular reaction with liver transplantation as the sole therapeutic option. PSC patients are at high risk of auto-immune comorbidities like irritable bowel disease (IBD), found in up to 80% of PSC patients (PSC-IBD). There are indications of genetic and environmental components for auto-immune development in IBD; however, its etiology remains unclear. Mast cells (MCs) infiltrate the liver and can become activated leading to degranulation and release of mediators, like histamine (HA), which result in increased intrahepatic bile duct mass, biliary senescence, hepatic inflammation, and hepatic stellate cell activation. Similarly, MCs infiltrate the intestine and increase inflammation which alters host-microbiome communication. MCs are necessary for successful liver regeneration and the combat of intestinal pathogens; however, chronic HA signaling exacerbates damage in cholangiopathies and IBD. Bile acid synthesis is tightly regulated by Farnesoid X Receptor (FXR) and its downstream mediator, fibroblast growth factor 15 (FGF15, -19 in humans). Cholangiocytes (i) are the target of cholangiopathies, (ii) modify and recycle bile acids through Apical Sodium Bile Acid Transporter (ASBT)-mediated cholehepatic shunting, which functions outside of enterohepatic circulation of bile acids and (iii) are capable of autocrine HA signaling. The complex relationship between hepatic and intestinal MC infiltration and bile acid signaling has not been established; therefore, identifying MC regulation of bile acid pool and FXR/FGF15 signaling pathway will provide insight into therapeutic treatment of PSC-IBD. Under the rationale that (i) cholestatic liver diseases are positively correlated with auto-immune comorbidities like IBD, (ii) during disease, MCs infiltrate the liver and intestine and release signaling factors like HA, and (iii) MCs express FXR and secrete FGF15/19; we propose the central hypothesis that MC activation regulates bile acid signaling and PSC progression through paracrine crosstalk with cholangiocytes in the liver and intestinal inflammation.
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    Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling
    (Wiley, 2021-11) Meadows, Vik; Kennedy, Lindsey; Ekser, Burcin; Kyritsi, Konstantina; Kundu, Debjyoti; Zhou, Tianhao; Chen, Lixian; Pham, Linh; Wu, Nan; Demieville, Jennifer; Hargrove, Laura; Glaser, Shannon; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Background & Aim Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15). Primary sclerosing cholangitis (PSC) patients typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile duct ligated (BDL) MC-deficient mice (KitW-sh), ductular reaction (DR) and liver fibrosis decrease compared to BDL WT; and MC injection exacerbates liver damage in normal mice. Approach & Results In this study, we demonstrated that MC-FXR regulates biliary FXR/FGF15, DR, hepatic fibrosis and alters intestinal FXR/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared to control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in PSC and PSC-IBD patients compared to healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence/senescence associated secretory phenotype (SASP), fibrosis and histamine in KitW-sh mice. Inhibition of MC-FXR prior to injection reduced these parameters. BDL and KitW-sh mice injected with MCs displayed increased TBA content, biliary FXR/FGF15 and intestinal inflammation, which decreased in BDL KitW-sh and KitW-sh mice injected with MC-FXR. MCs increased ileal FXR/FGF15 expression in KitW-sh mice that was reduced following FXR inhibition. BDL and Mdr2-/- mice, models of PSC, displayed increased intestinal MC infiltration and FXR/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in Mdr2-/- mice. In vitro, MC-FXR inhibition decreased biliary proliferation/SASP/FGF and hepatic stellate cell activation. Conclusion Our studies demonstrate the novel findings that MC-FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR/FGF15 signaling.