leptin and Cholestasis

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

Topics: Animals; Antibodies, Neutralizing; Cholestasis; Cytokines; Disease Models, Animal; Female; Hepatic Stellate Cells; Hyperplasia; Inflammation; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; Receptors, Leptin

To measure serum leptin concentration in dogs with pituitary-dependent hyperadrenocorticism and varying degrees of cholestatic disease and determine whether serum levels differed between dogs with pituitary-dependent hyperadrenocorticism and those with gall bladder mucocoele.. Client-owned healthy dogs (n=20), dogs diagnosed with gall bladder mucocoele (n=20) and dogs diagnosed with pituitary-dependent hyperadrenocorticism (n=60) were enrolled. Only dogs of normal body condition score were included. Dogs with pituitary-dependent hyperadrenocorticism were divided into three groups according to the severity of cholestatic disease: normal gall bladder (n=20), cholestasis (n=20) and gall bladder mucocoele (n=20). Serum leptin levels were measured using sandwich enzyme-linked immunosorbent assay.. Serum concentrations of leptin were similar between dogs with gall bladder mucocoele and those with pituitary-dependent hyperadrenocorticism accompanied by gall bladder mucocoele; these concentrations were significantly higher than those in healthy control dogs. In dogs with pituitary-dependent hyperadrenocorticism, circulating leptin concentration significantly increased with the severity of cholestasis: higher in the cholestasis group than the normal gall bladder group and higher in the gall bladder mucocoele group than the cholestasis group.. Elevated circulating leptin concentration was associated with canine pituitary-dependent hyperadrenocorticism and gall bladder mucocoele. Homeostatic imbalance of leptin concentration might be associated with severity of cholestatic disease in pituitary-dependent hyperadrenocorticism.

Topics: Adrenocortical Hyperfunction; Animals; Cholestasis; Dog Diseases; Dogs; Hydrocortisone; Leptin; Pituitary ACTH Hypersecretion

Cytokines may play an important role as inflammatory factors in liver diseases. There is some evidence suggesting a link between adiponectin-biliary function and liver disease. The aim of this study was to clarify the behavior of adipokines in autoimmune hepatitis type 1.. We assessed the circulating levels of adiponectin, tumor necrosis factor-alpha, resistin and leptin in 42 patients with autoimmune hepatitis, comparing them with 42 healthy subjects who were matched for age and sex and with 31 patients with nonalcoholic steatohepatitis (NASH), evaluating the associations with markers of cytolysis, cholestasis, and histological severity.. Adiponectin and TNF-alpha values were higher in patients compared to controls. The patients showed significantly higher Homeostasis Model Assessment values, suggesting an increased insulin resistance and serum levels of adiponectin positively correlated with gamma-glutamyltranspeptidase and alkaline phosphatase values after a simple regression analysis. Serum levels of resistin positively correlated with elevated aminotransferases and bilirubin values, and serum levels of TNF-alpha positively correlated with elevated alanine-aminotransferase and resistin values. The concentration of adiponectin increased significantly with staging of the disease. Patients with NASH showed lower levels of adiponectin and higher levels of resistin than AIH patients and controls.. Patients with AIH showed significantly higher adiponectin concentrations than controls despite their higher HOMA-IR values. The significant correlation between adiponectin levels and serological features of cholestasis suggested an association with biliary function. Our results indicate that adiponectin may be a possible marker for disease progression in AIH.

Topics: Adipokines; Adiponectin; Adult; Aged; Biomarkers; Cholestasis; Disease Progression; Fatty Liver; Female; Hepatitis, Autoimmune; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Resistin; Transaminases; Tumor Necrosis Factor-alpha

Recently leptin, a protein released from adipocytes, has been identified as a potent circulating satiety factor. We therefore undertook this series of experiments to examine leptin's role in the anorexia associated with biliary obstruction.. Rats underwent either surgical bile duct resection (BDR) or sham resection (sham). Body weight, and food and water intake were measured during a baseline period and for 8 days after surgery. At 4, 8 and 16 h as well as on days 2, 4, 6, and 8 postsurgery, sham and BDR rats were sacrificed and sera collected for subsequent measurement of leptin hormone concentration by RIA. White adipose tissue was collected on days 2, 4, 6 and 8 for leptin mRNA determination by Northern blot.. Obstructive cholestasis in BDR rats caused significant anorexia for up to 7 days post-surgery, whereas in sham rats, a significant decrease in food intake was only observed in the first 24-h period following surgery. In both sham and BDR rats, water intake was significantly decreased during the first 24-h period after surgery, but had recovered to baseline levels by day 2 in both groups. Fat pad mass corrected to body weight was not significantly different between the two experimental groups. Serum leptin levels were significantly increased 4 and 8 h after surgery, had normalized by 16 h post-surgery, and were then decreased in BDR rats on days 2, 4, 6 and 8 compared with controls. Leptin mRNA levels in epididymal fat pads were decreased by approximately 2-fold in BDR rats compared with sham rats on days 2, 4, 6 and 8. Furthermore, day 5 BDR and sham rats demonstrated similar anorectic responses to centrally administered leptin.. Leptin production is significantly increased early after biliary obstruction but is reduced after prolonged biliary obstruction. Increased circulating leptin levels may contribute to the profound anorexia observed early after biliary obstruction but appear not to mediate the anorexia observed during more chronic biliary obstruction.

Topics: Acute Disease; Adipose Tissue; Animals; Anorexia; Cholestasis; Chronic Disease; Drinking; Eating; Epididymis; Interleukin-6; Leptin; Male; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha