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 pro-gression 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 po-tential of microRNAs in cholangiopathies.

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.

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 and WT 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 marrow-derived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3+/-mice displayed increased severity of liver inflam-mation 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.