leptin and Cholelithiasis

Bile acid metabolism is a contributing factor that promotes cholelithiasis. Recent studies have suggested novel roles of leptin in the formation of gallbladder stones (GS); however, no evidence confirmed the function of leptin in the formation of primary intrahepatic bile duct stones (PIBDS) . In the current study, the liver tissues of patients with GS and PIBDS were collected to check the mRNA and protein expression levels of BSEP.. L02 cells stimulated with leptin were served for the expression of OB-Rb, AMPKα2, and BSEP by quantitative-polymerase chain reaction (q-PCR), Western blot, and immunohistochemistry, respectively.. The results showed that the level of serum leptin was higher in the GS group than in the control and PIBDS groups. Compared with the control group, the expression levels of OB-Rb, p-AMPKa2, and BSEP decreased significantly in the GS and PIBDS groups. In vitro, compared with the control cells, the protein levels of OB-Rb, p-AMPKa2, and BSEP increased in the L02 cells cultured with leptin. However, these enhancements disappeared when the cells were co-cultured with leptin plus Compound C.. The present results suggest that cholelithiasis, especially the formation of PIBDS, was connected with leptin, which could regulate bile acid metabolism through the OB-Rb/AMPKa2/BSEP signaling pathway.

Topics: Adult; Aged; AMP-Activated Protein Kinases; ATP Binding Cassette Transporter, Subfamily B, Member 11; Bile Acids and Salts; Bile Ducts, Intrahepatic; Cell Line; Cholelithiasis; Cross-Sectional Studies; Energy Metabolism; Female; Gallstones; Hepatocytes; Humans; Leptin; Liver; Male; Middle Aged; Receptors, Leptin; RNA, Messenger; Signal Transduction

Leptin has been shown to have various physiological and pathological roles in the canine gallbladder. In this study, we performed pre- and postoperative short-term follow-up analyses to confirm changes in serum leptin levels before and after cholecystectomy due to gallbladder mucocele (GBM) or cholelithiasis in dogs.. Twenty-six cholecystectomized dogs (GBM: n = 14; cholelithiasis: n = 12) for prophylactic or clinical symptom relief were enrolled in the present study. Dogs were subgrouped according to clinical symptoms and prognosis after surgery as follows: 1) asymptomatic group (n = 13), 2) recovery group (n = 8), and 3) death group (n = 5). Liver enzymes, total bilirubin, lipid profiles, and leptin concentrations were determined from sera on the pre-operative day and at 1, 3, and 7 days postoperation. Serum leptin concentrations were gradually but significantly decreased in the asymptomatic group (p = 0.008, 0.004, and 0.004 on days 1, 3, and 7, respectively, compared with that before surgery) and the recovery group (p = 0.048 and 0.048 on days 3 and 7, respectively, compared with that before surgery). However, in the death group, leptin concentrations did not differ significantly over time (p = 0.564). Additionally, serum leptin levels in the recovery group (p = 0.006) and death group (p = 0.021) were significantly higher than those in the asymptomatic group. Liver enzymes and total bilirubin (T-Bil) were significantly decreased only in the recovery group, particularly on day 7. In the asymptomatic group, liver enzymes and T-Bil were not changed significantly over time, and in the death group, only T-Bil was significantly decreased on day 7. Total cholesterol and triglyceride levels were not significantly decreased over time in all groups.. These results indicate that leptin is a potential biomarker reflecting the severity and prognosis of GBM and cholelithiasis both before and after cholecystectomy in dogs.

Topics: Animals; Cholecystectomy; Cholelithiasis; Dog Diseases; Dogs; Female; Gallbladder Diseases; Leptin; Male; Mucocele; Postoperative Period; Preoperative Period; Prognosis

Leptin and its receptor play several physiological roles in the canine gallbladder, and the dysregulation of leptin might play a role in the pathogenesis of gallbladder diseases such as gallbladder mucocele. Previous studies revealed a positive association between hyperlipidemia and gallstones in humans. However, the latter is still unclear in dogs with cholelithiasis. In this study, we examined the differences in leptin, leptin receptor, total cholesterol, and triglyceride levels between healthy dogs and dogs with cholelithiasis, and evaluated the correlation between leptin and hyperlipidemia. Twenty-eight healthy dogs and 34 client-owned dogs with cholelithiasis were enrolled in the study. Leptin concentrations and lipid profiles were determined from sera, and leptin and leptin receptor expression levels were quantified in gallbladder tissue. In dogs with cholelithiasis, serum concentrations of leptin (p < 0.001), total cholesterol (p < 0.001), and triglycerides (p < 0.001) were significantly higher compared with those in healthy dogs. Positive correlations were observed between serum leptin and total cholesterol (95% confidence interval (CI) = 0.61-0.89, r = 0.725, p < 0.001), and between leptin and triglycerides (95% CI = 0.63-0.89, r = 0.782, p < 0.001) in the cholelithiasis group. Hypercholesterolemia (Odds Ratio (OR) = 9.720; 95% CI = 1.148-82.318) and hypertriglyceridemia (OR = 12.913; 95% CI = 1.548-107.722) were shown to be risk factors for gallstone disease. In cholelithiasis patients who underwent cholecystectomy, serum leptin levels were significantly higher than in patients that had not undergone surgery (p < 0.001). Leptin and leptin receptor expression was upregulated in the gallbladder tissues of cholelithiasis patients (p < 0.01 and p < 0.001, respectively). These results indicate that increased serum leptin concentrations and hyperlipidemia (hypercholesterolemia or hypertriglyceridemia) are associated with canine cholelithiasis and that homeostatic imbalance of these parameters might affect the pathogenesis of gallstones.

Topics: Animals; Cholelithiasis; Dog Diseases; Dogs; Hyperlipidemias; Leptin

Leptin and its receptor play a role in several disease processes such as pancreatitis and heart disease. However, their association with gallbladder mucocele (GBM) in dogs has not been reported.. To evaluate differences in the expression of leptin and leptin receptor between dogs with and without GBM.. Twenty-five healthy dogs, including 9 laboratory beagle dogs, and 22 client-owned dogs with GBM.. Serum leptin concentration was determined in blood samples of all dogs by ELISA. Canine gallbladder samples were collected from 9 dogs with GBM that underwent surgery for therapeutic purposes and from 9 healthy laboratory beagle dogs as a normal control group. Samples were analyzed for leptin and leptin receptor mRNA by real-time polymerase chain reaction.. Serum leptin concentration was significantly higher in dogs with GBM than in healthy dogs (medians of 7.03 and 2.18 ng/mL, respectively; P < .001). Patients with GBM that had undergone surgery had significantly higher serum leptin concentrations than those that had not (medians of 12.2 and 4.09 ng/mL, respectively; P = .001). However, no difference in serum leptin concentration was found between dogs with GBM with or without endocrinopathies. The mRNA expression levels of leptin and its receptor were significantly increased in the gallbladder tissues of dogs with GBM.. Dysregulation of leptin might be involved in the pathophysiology of GBM, and leptin concentrations might be associated with GBM severity.

Topics: Animals; Cholelithiasis; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Gallbladder; Leptin; Male; Pedigree; Receptors, Leptin

To determine the relationships between serum leptin and levels of lipoprotein(a) [Lp(a)], apolipoprotein A-1 (ApoA-1) and apolipoprotein B (ApoB) in patients with cholelithiasis.. Patients with ultrasound-confirmed cholelithiasis and controls frequency-matched for age, sex, body mass index, fasting blood glucose and haemoglobin A1c levels were recruited. Fasting blood samples from all study participants were assayed for glucose, haemoglobin A1c, total cholesterol, high density lipoprotein-cholesterol (HDL-C) and triglyceride. Serum Lp(a), ApoA-1 and ApoB levels were measured using nephelometric assays; serum leptin was measured using an enzyme-linked immunosorbent assay.. A total of 90 patients with cholelithiasis and 50 controls were included in the study. Serum levels of leptin, Lp(a), total cholesterol, triglyceride and ApoB were significantly increased, and levels of ApoA-1 and HDL-C were significantly decreased, in patients with cholelithiasis compared with controls. Serum leptin in patients with cholelithiasis were significantly positively correlated with Lp(a) and ApoB and negatively correlated with ApoA-1.. Patients with cholelithiasis have higher leptin levels and an altered lipoprotein profile compared with controls, with increased leptin levels being associated with increased Lp(a) and ApoB levels, and decreased ApoA-1 levels, in those with cholelithiasis.

Topics: Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Body Mass Index; Cholelithiasis; Cholesterol, HDL; Female; Gallstones; Humans; Leptin; Male; Middle Aged

The association between insulin resistance, lipoproteins and leptin was evaluated in cholelithiasis. The study group included 55 women (68.8%) and 25 men (31.3%) with a mean age and SD of 50.56 +/- 14.28 yrs. The control group included 25 women (62.5%) and 15 men (37.5%) with a mean age of 50.93 +/- 11.73 yrs. Serum leptin levels were measured by the enzyme immunoassay method. HOMA-IR was determined by using fasting glucose and insulin levels. Insulin, total cholesterol (TC), LDL-C, HOMA-IR (p < 0.01) and leptin (p < 0.001) were significantly higher in the cholelithiasis group, compared to the controls. In patients with a HOMA-IR >2.2, age, body mass index (BMI), glucose, insulin, triglycerides (TG), TC and leptin levels were higher than in patients with a HOMA-IR < 2.2. In patients with glucose levels >100 mg/dl, mean BMI, HOMA-IR, insulin, TG, TC and leptin levels were significantly higher than in patients with glucose levels <100 mg/dl. In patients with TG levels >150 mg/dl, mean age, BMI, glucose, insulin, TC, leptin and HOMA-IR were significantly higher than in patients with TG levels < 150 mg/dl. In patients with BMI > 25 kg/m2, mean age, glucose, insulin, TG, TC, leptin, HOMA-IR were significantly higher than in patients with BMI < 25. In cholelithiasis group, there was a positive correlation between leptin and age, BMI, glucose, insulin, TG, TC, LDL-C or HOMA-IR. In conclusion, we found a positive association between increased leptin levels and abnormal lipoprotein metabolism in cholelithiasis. Cholelithiasis subjects with insulin resistance showed higher cardiometabolic risk factors than those without it.

Topics: Cholelithiasis; Female; Humans; Insulin Resistance; Leptin; Lipoproteins; Male; Middle Aged; Risk

A significant relationship exists among food intake and nutritional status and cholelithiasis, including gallstone and hepatolithiasis. Leptin is associated with obesity. This study was to investigate the differences in serum leptin levels in patients with gallstone and hepatolithiasis and to evaluate the relationships among leptin, cholecystokinin (CCK), lipid and lipoprotein concentrations.. Body mass index (BMI), serum leptin, CCK, insulin, lipid and lipoprotein concentrations, and liver function were measured in 382 patients with gallstone (GS group), 83 patients with hepatolithiasis (HS group) and 30 healthy controls (control group). The values of these indices were compared among the groups. In each group, Pearson's product-moment correlation coefficient among these indices were evaluated.. There were notable differences in serum leptin, CCK, total cholesterol, total triglycerides, apolipoprotein-a (APO-a), globulin, direct reacting bilirubin, and BMI between the GS and HS groups (P<0.05). Positive correlations between serum leptin and BMI, CCK, total cholesterol, gamma-glutamyl transpeptidase (GGT), aminotransferase, and insulin were found in the GS group (P<0.05). Positive correlations were observed between serum leptin and CCK, bilirubin, aminotransferase, GGT, in the HS group (P<0.05), but negative correlations between serum leptin and albumin or APO-a (P<0.05).. Leptin participates in modulating lipid metabolism. There are notable differences in leptin, serum lipid, and CCK between patients with gallstone and those with hepatolithiasis. The role of leptin in the pathophysiological course of cholelithiasis needs further investigation.

Topics: Adult; Aged; Apolipoproteins A; Bile Ducts, Intrahepatic; Bilirubin; Cholecystokinin; Cholelithiasis; Cholesterol; Female; Gallstones; Globulins; Humans; Leptin; Lipid Metabolism; Lipoproteins; Male; Middle Aged; Triglycerides

Human obesity is associated with leptin resistance and cholesterol gallstone formation. Previously, we demonstrated that leptin-resistant (Lep(db)) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite elevated serum cholesterol. Obese humans, however, consume a high cholesterol diet. Therefore, we hypothesized that on a high cholesterol diet, leptin-resistant mice would have cholesterol saturated bile and would form biliary crystals.. Eight-week old female lean control (n = 70) and leptin-resistant (n = 72) mice were fed a 1% cholesterol diet for 4 weeks. All animals then had cholecystectomies. Bile was collected, grouped into pools to determine cholesterol saturation index (CSI), and examined for cholesterol crystals. Serum cholesterol and leptin were also measured.. Gallbladder volumes for Lep(db) mice were enlarged compared with the lean mice (35.8 microl versus 19.1 microl, P < 0.001), but the CSI for the Lep(db) mice was lower than for the lean animals (0.91 versus 1.15, P < 0.03). The obese animals did not form cholesterol crystals, whereas the lean animals averaged 2.2 crystals per high-powered field (hpf) (P < 0.001). Serum cholesterol and leptin were also elevated (P < 0.001) in the obese animals.. These data suggest that Lep(db) obese mice fed a high cholesterol diet have increased gallbladder volume and decreased biliary cholesterol saturation and crystal formation despite elevated serum cholesterol compared with lean control mice. We conclude that the link among obesity, diet, and gallstone formation may not require hypersecretion of biliary cholesterol and may be related to the effects of diabetes, hyperlipidemia, or both on gallbladder motility.

Topics: Animals; Body Weight; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Crystallization; Dose-Response Relationship, Drug; Drug Resistance; Female; Gallbladder; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity

Increased cholesterol secretion is a major alteration of biliary function in obese subjects Leptin is a regulator of food intake and is increased in plasma of subjects with low energy expenditure and high adiposity. We investigated the relationship between leptin and the cholesterol saturation of bile in obese women before and after weight reduction by energy restriction (5.02 MJ/d). We studied women (n = 14) with a body mass index (BMI) > or = 30 kg/m(2) who were 35.4 +/- 2.3 y old and who did not have a history of gallstones. They were studied by ultrasound to ensure absence of stones or sludge. BMI, gallbladder bile composition, plasma leptin, serum lipids and lipoproteins cholesterol levels were recorded at baseline and after 6 wk of weight reduction. There were decreases in BMI (33.9 +/- 3.1 to 31.1 +/- 3.6 kg/m(2), P < 0.0001) and leptin levels (16.7 +/- 9.7 to 10.0 +/- 6.7 micro mol/L, P < 0.05) during weight loss. After the experimental period, there were positive correlations between plasma leptin levels and BMI (r = 0.71, P < 0.004); leptin levels and the cholesterol saturation index (CSI) (r = 0.53, P < 0.05); the CSI and LDL cholesterol (r = 0.73, P < 0.003); and negative correlations between leptin levels and HDL cholesterol (r = -0.54, P < 0.05) and LDL cholesterol (r = -0.57, P < 0.03). We have shown relationships among HDL cholesterol, CSI and leptin. This could be useful in understanding the pathophysiology of cholesterol gallstone formation in obese people.

Topics: Adult; Bile; Biomarkers; Body Mass Index; Cholelithiasis; Cholesterol; Female; Humans; Leptin; Lipids; Lipoproteins; Middle Aged; Obesity; Risk Factors; Weight Loss

The relationship between obesity and cholesterol cholelithiasis is not well understood at physiologic or genetic levels. To clarify whether obesity per se leads to increased prevalence of cholelithiasis, we examined cholesterol gallstone susceptibility in three polygenic (KK/H1J, NON/LtJ, NOD/LtJ) and five monogenic [carboxypeptidase E (Cpe (fat)), agouti yellow (A(y)), tubby (tub), leptin (Lep(ob)), leptin receptor (Lepr (db))] murine models of obesity during ingestion of a lithogenic diet containing dairy fat, cholesterol, and cholic acid. At 8 weeks on the diet, one strain of polygenic obese mice was resistant whereas the others revealed low or intermediate prevalence rates of cholelithiasis. Monogenic obese mice showed distinct patterns with either high or low gallstone prevalence rates depending upon the mutation. Dysfunction of the leptin axis, as evidenced by the Lep(ob) and the Lepr (db) mutations, markedly reduced gallstone formation in a genetically susceptible background strain, indicating that in mice with this genetic background, physiologic leptin homeostasis is a requisite for cholesterol cholelithogenesis. In contrast, the Cpe (fat) mutation enhanced the prevalence of cholelithiasis markedly when compared with the background strain. Since CPE converts many prohormones to hormones, a deficiency of biologically active cholecystokinin is a likely contributor to enhanced susceptibility to cholelithiasis through compromising gallbladder contractility and small intestinal motility. Because some murine models of obesity increased, whereas others decreased cholesterol gallstone susceptibility, we establish that cholesterol cholelithiasis in mice is not simply a secondary consequence of obesity per se. Rather, specific genes and distinct pathophysiological pathways are responsible for the shared susceptibility to both of these common diseases.

Topics: Animals; Bile; Cholelithiasis; Cholesterol; Disease Models, Animal; Female; Gallbladder; Genetic Predisposition to Disease; Leptin; Lipids; Liver; Male; Mice; Mice, Obese; Obesity

Obesity increases the risk of gallstones, especially in women. Most gallbladder disease studies have used body mass index (BMI) as a measure of overall adiposity, although BMI does not distinguish between fat and lean body mass. Central adiposity may also increase gallstone risk, although this is less well studied. Leptin is a peptide whose serum concentration is highly correlated with total body fat mass. We examined the relationship of gallbladder disease with anthropometric measures and serum leptin concentration in a large, national, population-based study. A total of 13,962 adult participants in the Third National Health and Nutrition Examination Survey underwent gallbladder ultrasonography and anthropometric measurements of BMI, body circumferences, and skinfold thicknesses, and a random subgroup of 5,568 had measures of fasting serum leptin concentrations. Gallstone-associated gallbladder disease was defined as ultrasound-documented gallstones or evidence of cholecystectomy. When controlling for BMI and other gallbladder disease risk factors in multivariate analysis, a test for trend for increasing waist-to-hip circumference ratio and risk of gallbladder disease was statistically significant among women (P =.043) and men (P =.007). BMI remained strongly associated with gallbladder disease among women (P <.001), but was unrelated among men (P =.46). Leptin concentration was associated with gallbladder disease in both sexes (P <.001), but not after controlling for BMI and waist-to-hip circumference in either women (P =.29) or men (P =.65). In conclusion, waist-to-hip circumference ratio was related to gallbladder disease among women and men. Serum leptin concentration was not a better predictor of gallbladder disease than anthropometry.

Topics: Adipose Tissue; Adult; Aged; Anthropometry; Body Constitution; Body Mass Index; Cholelithiasis; Fasting; Female; Gallbladder; Gallbladder Diseases; Humans; Leptin; Male; Middle Aged; Multivariate Analysis; Osmolar Concentration; Sex Characteristics; Skinfold Thickness; Ultrasonography