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Departments of Biomedical Research and Gastroenterology, Medica Sur Clinic & Foundation, Mexico City, Mexico
2To whom correspondence should be addressed. E-mail: nmendez{at}medicasur.org.mx.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSBiochemical analysesRESULTSDISCUSSIONLITERATURE CITED |
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30 kg/m2 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/m2, P < 0.0001) and leptin levels (16.7 ± 9.7 to 10.0 ± 6.7 µmol/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.
KEY WORDS: • obesity • cholesterol • leptin • gallstones • HDL cholesterol • women
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSBiochemical analysesRESULTSDISCUSSIONLITERATURE CITED |
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).
Obesity has been shown to be associated with supersaturation of bile with cholesterol because of an increased hepatic secretion of the sterol (2
–6
). Hypersecretion of biliary cholesterol can be due to several different mechanisms, including increased inflow of lipoprotein cholesterol to the liver, increased hepatic synthesis of cholesterol, decreased catabolism of cholesterol to bile acids and decreased rate of esterification of cholesterol in the liver. The first mechanism may be involved in obesity because HDL reduce serum cholesterol by facilitating cholesterol transport from peripheral tissues to the liver for secretion into bile. HDL are an important source of biliary cholesterol in both humans (7
) and animals (8
). Furthermore, in humans, low HDL cholesterol is often accompanied by hypertriglyceridemia, obesity and insulin resistance, and obese subjects characteristically have accelerated catabolism of HDL apolipoproteins (apo) (9
). A common belief is that low HDL cholesterol reflects increased core lipid exchange between HDL and triglyceride-rich lipoproteins, leading to modifications of HDL composition and size that result in the increased catabolism of HDL particles (10
).
On the other hand, leptin, the product of the ob gene, is an adipose tissue–derived hormone proposed to be the regulator of food intake (11
). Thus, failure to produce adequate amounts of leptin or resistance to its central actions could result in obesity (12
).
However, whether leptin is involved in biliary cholesterol secretion has been not explored in humans. The aim of this study was to investigate the role of leptin on cholesterol saturation of bile in obese women before and after weight reduction.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSBiochemical analysesRESULTSDISCUSSIONLITERATURE CITED |
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We recruited subjects from our medical center in Mexico City (Medica Sur Clinic & Foundation). Obese women were informed of the risk of gallstone formation while dieting and were asked whether they would participate in a study of gallstone prevention. To be accepted into this trial, subjects had to 1) have a body mass index (BMI)3
30 kg/m2; 2) be 20–60 y old; 3) be willing to participate in the diet plan for 6 wk; and 4) have normal serum potassium and calcium levels. Women of childbearing age had to have a negative serum pregnancy test. Patients were excluded from the study if they had any of the following: previous cholecystectomy; gallstone or gallbladder sludge on first ultrasonogram; a history of hypothyroidism or Cushing syndrome; an eating disorder or other psychological problem that would interfere with participation in the diet program; use of oral bile acid preparations, aluminum-based antacids, or lithium; long-term use of nonsteroidal anti-inflammatory agents (including aspirin) or antihyperlipidemic agents (including cholestyramine) within two weeks of entering into the trial; and a total bilirubin level >20 mg/L. Diuretic therapy had to have been discontinued at least 1 d before trial entry.
A total of 14 consecutive women who met all entry criteria and agreed to participate were enrolled in the trial. The study was approved by the Human Subjects Committee at The Medica Sur Clinic & Foundation as conforming with the ethical guidelines of the 1975 Declaration of Helsinki, and written informed consent was obtained from all participants before entry.
Study design.
Subjects received a low energy (5.02 MJ/d) diet. Treatment was considered to begin on the day on which energy restriction began and continued for 6 wk without interruption.
Weight-loss program.
The subjects underwent the Department of Program Control’s standard history taking and physical examination, as well as laboratory tests including a complete blood count, measurement of electrolytes, liver function tests, measurement of fasting lipids, thyroid-function tests and electrocardiography. They consumed a food-based diet (5.02 MJ) consisting of 20% fat, 60% carbohydrates, 20% protein and 1 L of water daily. Diets contained the following: carbohydrates, 195.6 g/d; total fat, 26.4 g/d (saturated fat, 7.6 g/d; polyunsaturated fat, 2.3 g/d; monounsaturated fat, 3.1 g/d); cholesterol, 73.8 mg/d; fiber, 30.2 g/d; iron,14.2 mg/d; sodium, 873.2 mg/d; zinc, 18.5 mg/d; magnesium, 377.6 mg/d; calcium, 1060.1 mg/d; vitamin C, 54.8 mg/d.
Experimental procedures.
Real-time ultrasonographic studies were conducted before and after the weight loss in women who had fasted overnight. Gallstones were defined by the presence of strong intraluminal echoes that were gravity dependent or that attenuated ultrasound transmission (acoustic shadowing). Sludge was defined as diffuse, low amplitude, homogeneous or heterogeneous nonshadowing echoes forming a fluid-fluid level. When each woman had completed the study, all ultrasonographic studies were evaluated again by the same radiologist. No discrepancies were found between the results of the first and second evaluations. In the second evaluation, all studies for each woman were viewed without subject identification.
Bile analysis.
All women had an endoscopy to obtain bile for analysis before beginning energy restriction and at the completion of the trial. Each woman had a routine upper endoscopy while under conscious sedation (midazolam, 2–4 mg) in the morning after an overnight fast. The tip of the endoscope was advanced into the second portion of the duodenum, and Vater’s ampulla was visualized. Bile samples were obtained by stimulating contraction of the gallbladder using an intraduodenal infusion of 30 mL of an 80 g/L amino acid solution. A 20- to 30-mL sample of concentrated bile was usually obtained. Any diluted bile obtained before the appearance of dark bile was discarded. Bile specimens were collected on ice and immediately transported to the laboratory where they were frozen and stored at -20°C for further lipid analyses as single batch.
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Biochemical analyses |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSBiochemical analysesRESULTSDISCUSSIONLITERATURE CITED |
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Total phospholipid levels were determined by the Bartlett method (13
). Cholesterol was determined in whole bile, after appropriate dilution, with an assay kit (Sigma Chemical, St. Louis MO). Total bile salt concentration was analyzed enzymatically using Turley’s method (14
). The cholesterol saturation index (CSI) of each bile sample was calculated from tables developed by Carey (15
).
Plasma leptin.
Leptin was determined by RIA using a human leptin RIA kit (Linco Research, St. Charles, MO). The within-assay analytical CV ranged from 3.4 to 8.3%, and the between-assay CV ranged from 3.6 to 6.2%.
Serum lipids, apoA-1 and apoB.
Serum cholesterol and triglycerides were determined before and after treatment. Serum total cholesterol was measured using the monotest cholesterol kit provided by Lakeside Laboratories of Mexico (Mexico City) (16
). Serum triacylglycerol concentrations were determined using an enzymatic method (17
). Triacylglycerols were completely hydrolyzed and the liberated glycerol determined by colorimetry. HDL were separated from VLDL and from LDL by precipitation with phosphotungstic acid (18
). The LDL were precipitated by adding polyvinyl sulfate to the sample and the LDL cholesterol (LDL-C) concentration was calculated from the difference between total cholesterol and the cholesterol in the supernatant after centrifugation. HDL cholesterol (HDL-C) and LDL-C were determined as indicated previously (16
). VLDL cholesterol was calculated as the difference between total plasma cholesterol and LDL-C + HDL-C (19
). The accuracy of HDL-C and LDL-C measurements was verified using control sera as indicated by the manufacturer (Lakeside Laboratories). Serum apoA-1 and apoB levels were measured before and after treatment by a turbidimetric method (20
).
Statistical analysis.
Changes over time were analyzed with a paired Student’s t test. Pearson’s product moment correlation was used to estimate linear relationships between variables (21
). Differences were considered significant when P < 0.05. Values in the text are means ± SD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSBiochemical analysesRESULTSDISCUSSIONLITERATURE CITED |
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).
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At baseline, plasma leptin levels and serum LDL-C levels were negatively correlated (r = -0.57, P < 0.03). However, after the experimental period, plasma leptin levels and BMI (r = 0.71, P < 0.004), and CSI (r = 0.53, P < 0.05) were positively correlated. In addition, plasma leptin levels and HDL-C were negatively correlated (r = -0.54, P < 0.05) and CSI and LDL-C (r = 0.73, P < 0.003) were positively correlated. None of the women had gallstones after energy restriction.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSBiochemical analysesRESULTSDISCUSSIONLITERATURE CITED |
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–24
). In this study, we found a significant decrease in BMI and plasma leptin levels after 6 wk of energy restriction.
Our aim was to investigate the role of leptin in controlling the cholesterol saturation of bile in obese subjects. Interestingly, there was a close relationship between plasma leptin levels and the biliary CSI but only after energy restriction, not at the baseline. In other words, plasma leptin levels are increased when the CSI is increased, as occurs in obese patients. How could leptin influence the cholesterol saturation of bile in obese patients? Obesity is associated with low HDL-C concentrations, believed to be the major lipoprotein source for biliary cholesterol (9
). According to current information (25
), it is more likely that alterations in lipoprotein metabolism are involved in biliary cholesterol secretion in obese patients and could explain this in part. For example, two monogenic mouse obesity models, ob/ob and db/db, have greatly elevated plasma HDL-C levels (26
) This contrasts with obese humans who have low HDL-C (27
). The ob/ob mice have a nonsense mutation in the leptin gene (27
), and db/db mice have a splicing defect in the gene encoding the leptin receptor (28
), resulting in defective leptin production and signaling, respectively. Interestingly, the defect in plasma HDL-C levels can be reversed by treatment of ob/ob mice with leptin. Moreover, treatment of lean wild-type mice with leptin also decreases plasma HDL-C and apoprotein levels. Because ob/ob and db/db represent specific mutations in leptin and its receptor, these findings suggest that leptin might play a role in the regulation of HDL apo and cholesterol metabolism. In addition, Cohen et al. (29
), in an experimental study on Zucker rats that are homozygous for a missense mutation in the leptin receptor, found that the administration of pharmacologic doses of leptin significantly increased biliary cholesterol secretion, as well as phospholipid secretion. They concluded that leptin might promote biliary cholesterol elimination in obese rats.
In this study, we found that HDL-C did not change after the 6-wk experimental period, and that the concentrations were in the normal range, whereas the apoA-I concentration was significantly lower after the experimental period. We also found a negative correlation (r = -0.54), between leptin and HDL-C levels, suggesting that when HDL-C levels are low, leptin levels are increased, as occurs in obese subjects. Although the comparison of the present results with those from experimental studies may be useful, we must recognize that there are many differences in lipoprotein metabolism between mice and humans. These include the presence of cholesteryl ester transfer protein in humans, which mediates core lipid exchange between HDL and triglyceride-rich lipoproteins (30
), and the absence of a correlation between HDL-C and apoA-II levels in humans (9
). However, it is striking that the high HDL phenotype of ob/ob mice is opposite to that in obese humans. Because obese humans usually have elevated plasma leptin levels (24
) and some form of central resistance to leptin has been postulated (31
), this raises the intriguing possibility that in obese humans, there could be direct peripheral actions of elevated leptin on the liver (32
,33
), leading to accelerated hepatic degradation of apo-HDL. Alternatively, there could be central effects of elevated leptin levels that influence HDL metabolic pathways.
Schwartz et al. (7
,34
) first demonstrated that the cholesterol used for biliary steroid secretion is derived primarily from plasma lipoprotein–free cholesterol (FC) rather than from cholesteryl ester. By injecting [3H] FC- or [14C] FC-labeled HDL and LDL simultaneously into bile fistulated patients, these investigators showed that a much larger fraction of HDL FC than of LDL FC is used for biliary secretion and that the radioactivity of HDL FC appears and peaks in bile much faster than that of LDL (9
,35
). In addition, Ji et al. (36
) provided evidence that a cell-surface HDL receptor is involved. Scavenger receptor class B type I (SR-BI) has recently been identified as an authentic HDL receptor that mediates the selective uptake of HDL cholesteryl ester (37
). SR-BI has high affinity for HDL (37
) and greatly accelerates the transport of HDL-FC across the liver into bile.
On the other hand, LDL-C and total cholesterol levels in persons losing weight are decreased (38
), and this is associated with the decrease in body weight. Consistent with these findings, we observed a decrease in serum LDL-C and total cholesterol after the weight loss period. At the same time, there was a positive correlation between serum LDL-C levels and the biliary CSI. We also found a negative correlation between serum LDL-C levels and plasma leptin at baseline. These findings suggest that LDL are another source of biliary cholesterol in obese people. Leptin may also be modulating the uptake of LDL at the hepatic level in humans. In fact, SR-BI also binds to LDL and possibly other lipoproteins, but with lower affinity (39
), which may account for the less favorable utilization of FC from other lipoproteins for biliary secretion (40
).
Finally, a previous study exploring the role of leptin as an indicator of adiposity and its relation to gallstone disease in a Mexican-American population reported that leptin levels were significantly related to gallstone disease, especially in women (41
). Interestingly, Ruhl and Everhart (42
) examined the relationship of gallbladder disease with anthropometric measures and serum leptin concentration in a large, national, population-based study in the Third National Health and Nutrition Examination Survey. They found that leptin concentration (10.7–16.2 µmol/L) was associated with gallbladder disease in both sexes (P < 0.001), but not after controlling for BMI and waist-to-hip circumference in women (P = 0.29) or men (P = 0.65). In addition, an experimental study that explored the role of bile acids on leptin gene expression in rats concluded that bile acids upregulate leptin gene expression indirectly, probably via effects on the absorption of dietary lipids (43
).
In conclusion, the present study has revealed the existence of relationships among serum HDL-C, the biliary cholesterol saturation index and plasma leptin in obese subjects. These preliminary results may lead to a better understanding of the regulation of biliary cholesterol metabolism, and this in turn could be useful in the prevention of cholesterol gallstone formation in obese subjects.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; BMI, body mass index; CSI, cholesterol saturation index; FC, free cholesterol; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; SR-BI, scavenger receptor class B type I.
Manuscript received 30 November 2001. Initial review completed 29 January 2002. Revision accepted 15 May 2002.
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