Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology

Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases

A Clinical study on Prevalence of Hypothyroidism in Diagnosed Cases of Gall Stones

INTRODUCTION: The explanations for possible relationship between hypothyroidism and gall stones are. 1. Disturbance of lipid metabolism in hypothyroidism causes increase in serum cholesterol level which leads to supersaturation of bile with cholesterol. 2. Low bile flow in hypothyroid patients. 3. Sphincter of oddi has thyroxine receptors and thyroxine has direct prorelaxing effect on sphincter of oddi. 4. In hypothyroidism, the effect of UDP glucuronyl transferase get decreased. So increase in unconjugated bilirubin result in formation of pigment stones. 5. In animal model (Rabbits), thyroxine usage dissolves the fatty diet induced gall stones. AIMS OF THE STUDY: 1. To study the prevalence of hypothyroidism in patients diagnosed with cholelithiasis/ choledocholithiasis. 2. To assess if thyroid profile is warranted in patients with biliary stone disease. MATERIALS AND METHODS: This is a cross sectional study conducted in Tirunelveli medical college. 100 patients with USG evidence of cholelithiasis/ choledocholithiasis were evaluated with basic investigations and additionally thyroid function test and USG thyroid were done. Prevalence of clinical/subclinical hypothyroidism in biliary stone patients were studied. RESULTS: Among 100 patients, 27% were males; 73% were females. Most of the Gall stone patients were in the age group of 40-49 years. Male to female ratio: 1 : 2.7. Females were the predominant group. In 100 gall stone patients, 21 patients were found to be hypothyroid (21%), 79 patients (79%) found to be Euthyroid. Among 21 hypothyroid patients, 4 patients (19.1%) were males and 17 patients (80.9%) were females. Most of gall stone patients with hypothyroidism were found to be in the age group of 40-49 years of age. 18 patients (18%) had subclinical Hypothyroidism and gall stones. 3 patients (3%) had clinical Hypothyroidism). CONCLUSION: Hypothyroidism is one of the probable risk factor for developing biliary stones. Screening of biliary stone patient with TFT will help to detect undiagnosed hypothyroidism

Novel insights in the pathogenesis of primary biliary cholangitis and cholangiocarcinoma

El contenido del capítulo 2 está sujeto a confidencialidad por la autora. 215 p.Este trabajo de tesis doctoral se centra en el estudio de dos enfermedades biliares: la colangitis biliar primaria (del inglés primary biliary cholangitis, PBC) y el colangiocarcinoma (CCA).Por un lado, ya que el miR-506 se encuentra sobre-expresado la PBC (una enfermedad biliar asociada con procesos autoinmunes frente a los colangiocitos) y parece tener un papel fundamental en su etiopatogenia, se ha llevado a cabo un trabajo en el que se ha evaluado el papel del miR-506 en PBC.Por otro lado, se han llevado a cabo dos estudios en CCA, el cáncer que afecta a los colangiocitos. En concreto, un trabajo ha evaluado el papel de la activación de los receptores de ácidos biliares FXR y TGR5 mediante el uso de los agonistas específicos OCA (ácido obeticólico) e INT-777, respectivamente, debido a que los ácidos biliares están implicados tanto en el desarrollo como en la progresión del CCA.Finalmente, los factores de transcripción están involucrados en los procesos tumorales tales como el CCA, por lo que el tercer trabajo se ha centrado en el estudio de los factores de transcripción de tipo krüppel (KLFs) en el CCA y, más concretamente, en el factor KLF5, el cual parece participar en la progresión de diversos tipos de cáncer.BioDonostia : Instituto de investigación sanitaria , Osasun ikerketa institutua AECC: Asociación Española contra el Cánce

Regulation of Liver Fibrosis via Alteration of Hepatic Stellate Cell Activation During Liver Repair

Cholestatic liver diseases including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and alcoholic-induced hepatobiliary damage are growing problems in the United States as well as worldwide. There are no successful treatments for these diseases that ultimately develop into cirrhosis and end stage liver diseases with no treatment but liver transplantation. We used the cholestatic bile-duct ligated (BDL) mouse liver to examine treatment with small or large cholangiocytes, a mouse model that mimics some features of PSC to study treatment with stem cell-derived extracellular vesicles and a mouse model of alcoholic liver disease to show the important role of let-7. After treatment, liver tissues/cells were analyzed for fibrosis, inflammation, endodermal markers and hepatic stellate cell activation. Mechanisms of action were evaluated further in vitro through the use of hepatic cell lines. We showed that small cholangiocyte treatment reduced fibrosis, biliary mass and stellate cell activation through enhanced expression of FoxA2. We additionally showed that treatment of cultured human stellate cell lines with cholangiocyte supernatants from small cholangiocyte-treated BDL mice showed increased senescence and decreased fibrosis and inflammation. Stem cell-derived extracellular vesicle treatment reduced fibrosis, biliary mass and inflammation while increasing FoxA2 gene expression. Treatment of stellate cells with medium from cultured cholangiocytes treated with stem cell-derived extracellular vesicles decreased inflammatory and fibrosis markers and increased senescence. We further showed that knockdown of Lin28 in mice, increased let-7 expression, reduced fibrosis and steatosis and reduced mesenchymal markers in stellate cells but increased senescence. Taken together, these studies show that successful treatments can reduce fibrosis through alteration of stellate cell activation. These studies may provide important insights into future treatment options for cholestatic and alcoholic liver disease patients

The bile acid TGR5 membrane receptor: From basic research to clinical application

AbstractThe TGR5 receptor (or GP-BAR1, or M-BAR) was characterized ten years ago as the first identified G-coupled protein receptor specific for bile acids. TGR5 gene expression is widely distributed, including endocrine glands, adipocytes, muscles, immune organs, spinal cord, and the enteric nervous system. The effect of TGR5 activation depends on the tissue where it is expressed and the signalling cascade that it induces. Animal studies suggest that TGR5 activation influences energy production and thereby may be involved in obesity and diabetes. TGR5 activation also influences intestinal motility. This review provides an overview of TGR5-bile acid interactions in health as well as the possible involvement of TGR5 in human disease