Indiana University-Purdue University Indianapolis (IUPUI) / 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.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18147号 / 医博第3867号 / 新制||医||1002(附属図書館) / 31005 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 坂井 義治, 教授 千葉 勉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

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The thermogenic effects in hypothermia of four substrates--alanine, glycine, ethano, and pyruvate - were studied in seventeen experiments. Albino rats were decapitated, and their livers were removed. The livers were homogenized with phosphate buffer at -5° C. After equilibration in a refrigerated Warburg apparatus at 20° C, the substrates were added and tissue respiration was recorded over three hours. Heat production was calculated from O2 uptake and CO2 production. Results showed that alanine, glycine, and pyrvate yielded 93.19, 89.86, and 89.89 x 10^6 kg-cal compared to a control value of 86.11 x 10^-6 kg-cal. Ethanol provided 110.31 x 10^-6 kg-cal, a value significantly greater than for the other substrates. The substrates studied, especially ethanol, did, therefore increase heat production in an artificially hypothermic environment in homogenized rat livers.

Liver gene expression changes during development and is affected by growth hormone (GH). These changes in gene expression may be due to the differential expression of the liver-enriched transcription factors (LETFs). To study the potential involvement of LETFs in the regulation of gene expression in the bovine liver, we cloned the cDNA fragments of nine bovine LETFs, including hepatocyte nuclear factor (HNF)-1Æ Ã , 1Æ Ã , 3Æ Ã , 3Æ Ã , 3Æ Ã , 6, albumin D-element binding protein (DBP), and CCAAT/enhancer-binding proteins (C/EBP) -Æ Ã and Æ Ã , and compared the expression levels of them between adult and fetal bovine liver and between GH-treated and untreated adult bovine liver. The mRNA abundance of the LETFs was determined by ribonuclease protection assay (RPA). The cloned bovine LETF cDNA sequences showed high degrees of similarity (79 % to 99 %) to the LETF sequences of other species. The mRNA levels of HNF-1Æ Ã , HNF-3Æ Ã , and HNF-6 were significantly higher (P < 0.05) in the fetal liver (n=3) than in the adult liver (n=7). There were significant increases (P < 0.05) in the mRNA expression of HNF-3Æ Ã and HNF-6 in the liver of cows 24 h (n=6) and 1w (n=6) after GH administration. The results of this study suggest that HNF-1Æ Ã , HNF-3Æ Ã , and HNF-6 may play a role in differential regulation of gene expression between the fetal and adult bovine liver and that HNF-3Æ Ã and HNF-6 may be also involved in GH regulation of gene expression in the bovine liver. / Master of Science

published_or_final_version / Biochemistry / Master / Master of Philosophy

published_or_final_version / abstract / Biochemistry / Master / Master of Philosophy

published_or_final_version / abstract / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy