Over the last years,cholangiocytes,the cells that line the biliary tree,have been considered an important object of study for their biological properties which involves bile formation,proliferation,injury repair,fibro...Over the last years,cholangiocytes,the cells that line the biliary tree,have been considered an important object of study for their biological properties which involves bile formation,proliferation,injury repair,fibrosis and angiogenesis.Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration.During these processes,biliary cells start to secrete different cytokines,growth factors,neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells.Several studies suggest that hormones,and in particular,sex hormones,play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease.Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases.The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.展开更多
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 subt...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.展开更多
The liver has a vital role in many metabolic and regulatory processes in the body.Primary biliary cholangitis(PBC),previously known as primary biliary cirrhosis,is a chronic cholestatic autoimmune disease of the intra...The liver has a vital role in many metabolic and regulatory processes in the body.Primary 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 antigens.At 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 treatment.Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression.Currently,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus.This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.展开更多
Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver fibrosis.Bile duct epithelial cells,cholangiocytes,are a primary target for cholangiopathies.Ductular reaction i...Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver fibrosis.Bile duct epithelial cells,cholangiocytes,are a primary target for cholangiopathies.Ductular reaction is often observed in cholangiopathies and the proliferation of cholangiocytes is associated with ductular reaction and liver fibrogenesis.Accumulating evidence suggests that patients with chol-angiopathies have different gut bacterial profiles from healthy individuals,indicating the association between gut microbiota and cholangiopathies.Bile acids are produced by hepatocytes and modified by gut bacteria.Bile acids regulate cholangiocyte proliferation but effects vary depending on the type of bile acids.Recent 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 cohorts.This review summarizes current understandings of functional roles of gut bacterial imbalance and strategies for treatments of cholangiopathies targeting gut bacteria.展开更多
Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regu...Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.展开更多
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 epithelium.Cholangiopathies result in signific...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 epithelium.Cholangiopathies 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 diseases.MicroRNAs are a class of small,non-coding RNAs that regulate post-transcriptional mRNA expression of specific genes.The role of microRNAs has expanded to include the initiation and development of many diseases,including cholangiopathies.Understanding microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these diseases.In 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.展开更多
基金MIUR grants PRIN 2005 (prot. 2005067975_001) to E. Gaudio and Biomedicina, Cluster C04, Progetto n. 5 to E.Gaudio-P.Onori MIUR grants PRIN 2005 (prot.No: 2005067975_002) to D. Alvaro and a VA Research Scholar Award, a VA Merit Award and the NIH grants DK58411 and DK062975 to Gianfranco Alpini
基金a grant award from Scott & White Hospital and The Texas A&M University System Health Science Center, a VA Merit Award, a VA Research Scholar Award and the NIH grants DK58411 and DK062975 to Dr. Alpini, by grant awards to Shannon Glaser and Heather Francis from Scott & White Hospital.
基金Supported partly by the University Federate Athenaeum Funds from University of Rome "La Sapienza" and PRIN 2007 to Gaudio EUniversity Funds to Onori P,the Dr.Nicholas C Hightower Centennial Chair of Gastroenterology from Scott and White+3 种基金the VA Research Scholar Awarda VA Merit Awardand the NIH Grants DK58411,and DK76898 to Dr.Alpinia NIH RO1 Grant Award to Dr.Glaser(DK081442)a NIH K01Grant Award(DK078532)to Dr.DeMorrow
文摘Over the last years,cholangiocytes,the cells that line the biliary tree,have been considered an important object of study for their biological properties which involves bile formation,proliferation,injury repair,fibrosis and angiogenesis.Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration.During these processes,biliary cells start to secrete different cytokines,growth factors,neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells.Several studies suggest that hormones,and in particular,sex hormones,play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease.Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases.The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.
文摘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.
基金This work was supported by Texas A&M University,College of Medicine,Department of Medical Physiology,Bryan,TX,the NIH grants DK110035,DK129236,and AA028711 to Drs.Alpini,and Glaser,Cancer Prevention&Research Institute of Texas(CPRIT)-RP210213 to Dr.Chakrabortythe Hickam Endowed Chair,Gastroenterology,Medicine,Indiana University,the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative,the Senior Career Scientist Award(IK6 BX004601)the VA Merit award(5I01BX000574)to GA from the United States Department of Veteran’s Affairs,Biomedical Laboratory Research and Development Service.The views expressed in this article are those of the authors and do not necessarily represent the Department of Veterans Affairs views.
文摘The liver has a vital role in many metabolic and regulatory processes in the body.Primary 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 antigens.At 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 treatment.Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression.Currently,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus.This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.
基金This work was supported in part by the Dr.Nicholas C.High-tower Centennial Chair of Gastroenterology from Scott&White,a Veterans Health Administration Research Career Scientist award(IK6BX004601)a VA Merit award to Dr.G.Alpini(5I01BX000574)+1 种基金a VA Merit Award(1I01BX001724)to Dr.F.Meng from the United States Department of Veterans Affairs Biomedical Laboratory Researchthe USA National Institutes of Health(NIH)grants DK110035,DK054811,DK062975,DK115184,AA025997 and AA025157 to Drs.G.Alpini,F.Meng and S.Glaser.
文摘Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver fibrosis.Bile duct epithelial cells,cholangiocytes,are a primary target for cholangiopathies.Ductular reaction is often observed in cholangiopathies and the proliferation of cholangiocytes is associated with ductular reaction and liver fibrogenesis.Accumulating evidence suggests that patients with chol-angiopathies have different gut bacterial profiles from healthy individuals,indicating the association between gut microbiota and cholangiopathies.Bile acids are produced by hepatocytes and modified by gut bacteria.Bile acids regulate cholangiocyte proliferation but effects vary depending on the type of bile acids.Recent 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 cohorts.This review summarizes current understandings of functional roles of gut bacterial imbalance and strategies for treatments of cholangiopathies targeting gut bacteria.
基金This work was supported in part by the Hickam Endowed Chair,Gastroenterology,Medicine,Indiana University and the Indiana University Health e Indiana University School of Medicine Strategic Research Initiative,the Research Career Scientist to Dr.Alpini from the United States Department of Veteran’s Affairs,Biomedical Laboratory Research and Development Service and National Institutes of Health(NIH)grants DK054811,DK110035,and DK076898 to Drs.G.Alpini and S.Glaser.In addition,this work was supported in whole or in part by grants from the American Diabetes Association(ADA)(1-10-BS-76 to C.Wu)the National Institutes of Health(DK095828 and DK124854 to C.Wu).
文摘Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.
基金This work was supported in part by the Dr.Nicholas C.Hightower Centennial Chair of Gastroenterology from Scott&White,a VA Research Career Scientist Award,a VA Merit award to Dr.Alpini(5I01BX000574)a VA Merit Award(1I01BX003031)to Dr.Francis,a VA Merit Award(5I01BX002192)to Dr.Glaser+1 种基金a VA Merit Award(1I01BX001724)to Dr.Meng from the United States(U.S.)Department of Veterans Affairs Biomedical Laboratory Researcha NIH grant DK108959 to Dr.Francis,and the multiple-PIs NIH grants DK058411,DK076898,DK107310 and DK062975 belong to Drs.Alpini,Meng and Glaser.
文摘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 epithelium.Cholangiopathies 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 diseases.MicroRNAs are a class of small,non-coding RNAs that regulate post-transcriptional mRNA expression of specific genes.The role of microRNAs has expanded to include the initiation and development of many diseases,including cholangiopathies.Understanding microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these diseases.In 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.