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Bile acid interactions with cholangiocytes

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World Journal of Gastroenterology 2006年第22期12卷 3553-3563页

作者： Xuefeng Xia Heather Francis Shannon Glaser gianfranco alpini Gene LeSage University of Texas at Houston Medical School Houston TX United States Division of Research and Education Scott & White Hospital and The Texas A&M University System Health Science Center College of Medicine Temple TX United States Department of Medicine Division of Research and Education Scott & White Hospital and The Texas A&M University System Health Science Center College of MedicineTemple TX United States Central Texas Vctcrans Health Care System and Department of Medicine and Systems Biology and Translational Medicine United States

Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter （ASBT）（also referred to as Ibat; gene name Slc10a2） is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified （t-ASBT, multidrug resistance （MDR）3, an unidentified anion exchanger system and organic solute transporter （Ost） heteromeric transporter, Ostα- Ostβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3＇, 5＇monophosphate （cAMP）-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C （PKC）, phosphoinositide 3-kinase （PI3K）, mitogenactivated protein （MAP） kinase and extracellular signalregulated protein kinase （ERK） intracellular signals. Bile acids significantly alter cholangiocyte secretion,proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals,and in some instances trigger opposing effects on cholangiocyte secretion, pro

关键词： Cholangiocytes Bile acid Liver

Therapeutic Use of Viruses:Newcastle Disease Virus HK84 Oncolytic Treatment for Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2022年第5期10卷 783-785页

作者： Leonardo Baiocchi Heather Francis gianfranco alpini Unit of Hepatology Tor Vergata UniversityRomeItaly Division of Gastroenterology and Hepatology Department of MedicineIndiana University School of MedicineIndianapolisINUSA Research Richard L.Roudebush VA Medical CenterIndianapolisINUSA

Hepatocellular carcinoma(HCC)is the most frequent primary liver tumor worldwide and,despite regional therapeutic and diagnostic differences,it stands among the three most lethal cancers found in *** or ablative treatments,together with liver transplant,are the most successful clinical approaches,frequently ensuring complete HCC healing and the best survival ***,curative techniques are applicable only in patients at early stages of the disease(limits:one nodule≤5 cm in diameter or not more than three nodules all less than 3 cm in diameter).1 A significant percentage of HCC patients(≥50%)have a more advanced stage at diagnosis and must rely on less effective treatment or palliative care,thus signifying the need for alternative systemic ***,a tyrosine kinase inhibitor(TKI)was the first effective HCC drug treatment discovered after negative results were obtained with canonical cytotoxic *** 2018 lenvatinib,another TKI,was approved in the USA as a first line treatment for *** immunotherapy combining the checkpoint inhibitor,atezolizumab with the VEGF-antibody bevacizumab,has improved survival rates compared with previous TKI-based monotherapies.2 Despite treatment improvements,1-year survival is attained by only two-thirds of patients,thus prompting investigation of more effective therapies for advanced stage HCC.

关键词： Carcinoma healing diagnosis

c-Met targeted therapy of cholangiocarcinoma

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World Journal of Gastroenterology 2008年第19期14卷 2990-2994页

作者： Matei P Socoteanu Frank Mott gianfranco alpini Arthur E Frankel Scott & White Hospital and Clinics 5701 SAirport RdTemple

Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

关键词： Cholangiocarcinoma c-Met Chemotherapy Target therapy

Role of the melatonin/menin signaling in the regulation of cholangiocarcinoma growth

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Cancer Biology & Medicine 2018年第S1期15卷 3-4页

作者： Shannon Glaser gianfranco alpini Central Texas Veterans Health Care System Baylor Scott&White and Texas A&M UniversityTempleTexasUSA

Objective:There is decreased expression of arylalkylamine N-acetyltransferase(the rate-limiting enzyme regulating melatonin synthesis)and the clock gene,Per1 and increased expression of the MT1 melatonin receptor subtype in cholangiocarcinoma(CCA).This study tested the hypothesis that the inhibitory effects of the melatonin/MT1/Per1 axis on CCA growth are mediated by inhibition of miR-24.

关键词： Role melatonin regulation

Mechanisms of biliary carcinogenesis and growth

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World Journal of Gastroenterology 2008年第19期14卷 2986-2989页

作者： Candace Wise Metaneeya Pilanthananond Benjamin F Perry gianfranco alpini Michael McNeal Shannon S Glaser Systems Biology and Translational Medicine Scott and White Hospital and The Texas A&M University System Health Science Center Department of Medicine Scott and White Hospital and The Texas A&M University System Health Science Center The Texas A&M University System Health Science Center

Cholangiocarcinoma is a rare cancer originating from the neoplastic transformation of the epithelial cells (i.e. cholangiocytes) that line the biliary tract. The prognosis for patients with cholangiocarcinoma is grim due to lack of viable treatment options. The increase in world-wide incidence and mortality from cholangiocarcinoma highlights the importance of understanding the intracellular mechanisms that trigger the neoplastic transformation of cholangiocytes and the growth of biliary cancers. The purpose of the following review is to address what has been learned over the past decade concerning the molecular basis of cholangiocarcinogenesis. The material presented is divided into two sections:(1) mechanisms regulating neoplastic transformation of cholangiocytes; and (2) factors regulating cholangiocarcinoma growth. An understanding of the growth regulatory mechanisms of cholangiocarcinoma will lead to the identification of therapeutic targets for this devastating cancer.

关键词： Biliary carcinogenesis Cholangiocarcinomas Primary biliary cirrhosis Primary sclerosing cholangitis

Functional roles of gut bacteria imbalance in cholangiopathies

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Liver Research 2019年第1期3卷 40-45页

作者： Keisaku Sato Fanyin Meng Giammarco Fava Shannon Glaser gianfranco alpini Division of Research Central Texas Veterans Health Care SystemTempleTXUSA Baylor Scott&White Digestive Disease Research Center Baylor Scott&White Health CareTempleTXUSA Department of Medical Physiology Texas A&M University College of MedicineTempleTXUSA Ospedali Riuniti di Ancona AnconaItaly

Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver *** duct epithelial cells,cholangiocytes,are a primary target for *** reaction is often observed in cholangiopathies and the proliferation of cholangiocytes is associated with ductular reaction and liver *** evidence suggests that patients with chol-angiopathies have different gut bacterial profiles from healthy individuals,indicating the association between gut microbiota and *** acids are produced by hepatocytes and modified by gut *** acids regulate cholangiocyte proliferation but effects vary depending on the type of bile *** studies suggest that therapies targeting gut bacteria,such as antibiotics administration and gut bacteria depletion or therapies using gut bacteria-associated bile acids,such as ursodeoxycholic acid(UDCA)administration,may be useful for treatments of cholangiopathies,although data are contro-versial depending on animal models or *** review summarizes current understandings of functional roles of gut bacterial imbalance and strategies for treatments of cholangiopathies targeting gut bacteria.

关键词： Cholangiopathies Bile acids Gut bacteria Cholangiocytes Cholestasis Inflammation

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis

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Journal of Clinical and Translational Hepatology 2023年第4期11卷 949-957页

作者： Abigail Medford Jonathan Childs Ashleigh Little Sanjukta Chakraborty Leonardo Baiocchi gianfranco alpini Shannon Glaser Department of Medical Physiology Texas A&M University School of MedicineBryanTXUSA Hepatology Unit University of Tor VergataRomeItaly Division of Gastroenterology and Hepatology Department of MedicineIndiana University School of MedicineIndianapolisINUSA

The liver has a vital role in many metabolic and regulatory processes in the *** biliary cholangitis(PBC),previously known as primary biliary cirrhosis,is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial *** this time there is no definitive cure for PBC;however,ursodeoxycholic acid(UDCA)has been shown to reduce injury when administered as the first line of *** therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease ***,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable *** review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

关键词： Cholestatic liver disease Therapeutic approaches Biliary epithelia ursodeoxycholic acid

Heterogeneity of the intrahepatic biliary epithelium

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World Journal of Gastroenterology 2006年第22期12卷 3523-3536页

作者： Shannon Glaser Heather Francis Sharon DeMorrow Gene LeSage Giammarco Fava Marco Marzioni Julie Venter gianfranco alpini Department of Medicine Division of Research and Education Scott & White Memorial Hospital and The Texas A&M University System Health Science CenterCollege of MedicineTempleTXUnited States Sharon DeMorrow Division of Research and Education Scott & White Memorial Hospital and The Texas A&M University System Health Science CenterCollege of MedicineTempleTXUnited States University of Texas at Houston Medical School Houston TX.United States Department of Gastroenterology Universita Politecnica delle Marche Azienda Ospedaliera "Ospedali Riuniti di Ancona" Ancona Italy Department of Medicine Scott & White Memorial Hospital and The Texas A&M University System Health Science Center College of MedicineTempleTXUnited States Central Texas Veterans Health Care System Department of Medicine Systems Biology and Translational MedicineScott & White Memorial Hospital and The Texas A&M University System Health Science CenterCollege of MedicineTempleTXUnited States

The objectives of this review are to outline the recent findings related to the morphological heterogeneity of the biliary epithelium and the heterogeneous pathophysiological responses of different sized bile ducts to liver gastrointestinal hormones and peptides and liver injury/toxins with changes in apoptotic, proliferative and secretory activities. The knowledge of biliary function is rapidly increasing because of the recognition that biliary epithelial cells （cholangiocytes） are the targets of human cholangiopathies, which are characterized by proliferation/damage of bile ducts within a small range of sizes. The unique anatomy, morphology, innervation and vascularization of the biliary epithelium are consistent with function of cholangiocytes within different regions of the biliary tree. The in vivo models [e.g., bile duct ligation （BDL）, partial hepatectomy, feeding of bile acids,carbon tetrachloride （CCI4） or α-naphthylisothiocyanate（ANIT）] and the in vivo experimental tools [e.g., freshly isolated small and large cholangiocytes or intrahepatic bile duct units （IBDU） and primary cultures of small and large murine cholangiocytes] have allowed us to demonstrate the morphological and functional heterogeneity of the intrahepatic biliary *** models demonstrated the differential secretory activities and the heterogeneous apoptotic and proliferative responses of different sized ducts. Similar to animal models of cholangiocyte proliferation/injury restricted to specific sized ducts, in human liver diseases bile duct damage predominates specific sized bile *** studies related to the functional heterogeneity of the intrahepatic biliary epithelium may disclose new pathophysiological treatments for patients with cholangiopathies.

关键词： cAMP Gastrointestinal hormones Growth factors Mitosis Nerves

Diagnostic and therapeutic potentials of microRNAs in cholangiopathies

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Liver Research 2017年第1期1卷 34-41页

作者： Lindsey Kennedy Heather Francis Fanyin Meng Shannon Glaser gianfranco alpini Research Central Texas Veterans Health Care SystemTempleTXUSA Department of Medicine Texas A&M Health Science CenterCollege of MedicineTempleTXUSA Baylor Scott&White Digestive Disease Research Center Baylor Scott&White HealthTempleTXUSA

Cholangiopathies are a group of rare,devastating diseases that arise from damaged cholangiocytes,the cells that line the intra-and extra-hepatic bile ducts of the biliary *** result in significant morbidity and mortality and are a major cause of liver transplantation.A better understanding of the underlying pathogenesis that influences cholangiocyte dysregulation and cholangiopathy progression is necessary,considering the dismal prognosis associated with these *** are a class of small,non-coding RNAs that regulate post-transcriptional mRNA expression of specific *** role of microRNAs has expanded to include the initiation and development of many diseases,including *** microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these *** this review,the authors primarily focus on studies published within the last five years that help determine the diagnostic and therapeutic potential of microRNAs in cholangiopathies.

关键词： microRNAs Cholangiopathies Diagnosis Therapy