| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Lecithin hydrophobicity modulates the process of cholesterol crystal nucleation and growth in supersaturated model bile systems Ochi, H., S. Tazuma, et al. (1996), Biochem J 318 (Pt 1): 139-44. Abstract: The present study was performed to determine whether the degree of lecithin hydrophobicity regulates bile metastability and, therefore, affects the process of cholesterol crystallization. Supersaturated model bile (MB) solutions were prepared with an identical composition on a molar basis (taurocholate/lecithin/cholesterol, 73:19.5:7.5; total lipid concentration 9 g/dl) except for the lecithin species; egg yolk phosphatidylcholine, soybean phosphatidylcholine, 1-palmitoyl-2-linoleoyl-sn-phosphatidylcholine, dilinoleoyl phosphatidylcholine and dipalmitoyl phosphatidylcholine. Each MB solution was incubated and sequentially examined. Video-enhanced contrast microscopy demonstrated that the rate of vesicular aggregation and fusion correlated with the degree of lecithin hydrophobicity, and that the rate of cholesterol crystal nucleation correlated with the degree of lecithin hydrophilicity. In MBs containing less hydrophobic lecithin, needle-like crystals developed and transformed into mature plate-like crystals, whereas classical plate-like crystals were consistently observed in MBs composed of hydrophobic lecithin. Laser-diffraction particle size analysis demonstrated that the increase in lecithin hydrophobicity enlarged the vesicle dimension, enhancing its cholesterol-holding capacity. Correlation between vesicular cholesterol packing density and lecithin hydrophobicity suggests that the process of bile cholesterol nucleation and growth is regulated, in part, by acyl chain unsaturation in lecithin. Since the composition of biliary lecithins is responsive to dietary manipulations, this study provides new insights into the prevention of cholesterol gallstones. |
| Lecithin: cholesterol acyltransferase Harada, Y., I. Inoue, et al. (1994), Nippon Rinsho 52(12): 3158-63. Abstract: Lecithin:cholesterol acyltransferase (LCAT) is a plasma enzyme that catalyzes esterification of plasma lipoprotein unesterified cholesterol, and plays a central role in maintaining reverse cholesterol transport through action with high density lipoprotein (HDL) and Cholesterol ester transfer protein (CETP). Cloned cDNA sequence of LCAT, consisted of about 1400 base pair which codes 416 amino acids, revealed high content of alpha-helix and beta-sheet, identity of amino acid sequence with various lipases, and putative structure of catalytic sites and mechanism of enzymatic action is proposed. Close relationship between location of gene mutation and severity of clinical and biochemical characteristics revealed by gene analysis in patients of LCAT deficiency and Fish eye disease is summarized. |
| Lecithin: cholesterol acyltransferase deficiency: identification of two defective alleles in fibroblast cDNA Miller, M., K. Zeller, et al. (1995), J Lipid Res 36(5): 931-8. Abstract: Previous mutations associated with lecithin:cholesterol acyltransferase (LCAT) deficiency have been identified using genomic DNA. To facilitate mutation analysis, we used cDNA from cultured fibroblasts which were shown to express LCAT mRNA. Using reverse-transcriptase PCR, LCAT cDNA was obtained from a 13-year-old boy with complete LCAT deficiency, characterized by low HDL-C (3 mg/dl), nondetectable initial cholesterol esterification rate, LCAT activity, and minimal LCAT mass (0.16 vs. 5-7.5 micrograms/ml). Sequencing of LCAT cDNA clones identified two mutations. A novel frameshift mutations caused by deletion of cytosine at the third nucleotide position of amino acid 168 (exon 5) predicts a disrupted protein catalytic site by converting Ser181-->Ala and creates a Pvu-II restriction site prior to premature truncation at amino acid 238. A C-->T transition results in a substitution of methionine for threonine at amino acid position 321 and creates an Nla-III restriction site on the maternal allele. Expression studies of mutant LCAT cDNA confirmed the virtual absence of LCAT activity in transfected COS-1 cells. The molecular defect in a young male with complete LCAT deficiency has been identified using fibroblast cDNA. |
| Lecithin:cholesterol acyl transferase G30S: association with atherosclerosis, hypoalphalipoproteinemia and reduced in vivo enzyme activity Rosset, J., J. Wang, et al. (2001), Clin Biochem 34(5): 381-6. Abstract: OBJECTIVES: A 69 yr old male was referred for assessment of a very low plasma HDL cholesterol and apolipoprotein AI concentration. At age 65, he had undergone triple vessel coronary bypass graft surgery. He had a strong family history of early coronary heart disease. We analyzed the molecular basis of his clinical and biochemical abnormalities. DESIGN AND METHODS: We used DNA sequencing to determine whether mutations in LCAT were present. We also evaluated plasma biochemistry and LCAT activity. RESULTS: DNA sequencing revealed that the patient was a heterozygote for the G30S mutation in the gene encoding lecithin:cholesteol acyl transferase (LCAT). His plasma was found to have half-normal LCAT activity. CONCLUSIONS: The findings in this patient suggest that rare dysfunctional mutations in candidate genes, such as LCAT, can contribute to the spectrum of patients ascertained because of low HDL cholesterol. |
| Lecithin:cholesterol acyltransferase activity and high-density lipoprotein subfraction composition in type 1 diabetic patients with improving metabolic control Weight, M. J., H. S. Coetzee, et al. (1993), Acta Diabetol 30(3): 159-65. Abstract: On initial diagnosis or when metabolic control is poor, subjects with type 1 (insulin-dependent) diabetes mellitus often exhibit decreased high density lipoprotein (HDL) cholesterol levels, which have been associated in numerous studies in non-diabetic subjects with atherosclerosis and coronary artery disease. We measured the activities of plasma lecithin:cholesterol acyltransferase (LCAT), post-heparin lipoprotein lipase, and the composition of the HDL subfractions HDL2 and HDL3, in ten poorly controlled type 1 diabetic patients admitted to a metabolic ward (six women and four men, aged 18-37 years). The measurements were repeated after metabolic control had been optimised and again a week after discharge. The results were compared with those of ten healthy normolipidaemic subjects matched for age, sex and body mass. LCAT activity increased significantly (P < 0.05) with improved metabolic control in the diabetic patients, and showed positive within-person correlation with HDL2 cholesterol ester (r = 0.67; P < 0.01), HDL2 free cholesterol (r = 0.67; P < 0.01), phosphatidylcholine (r = 0.49; P < 0.05), total phospholipids (r = 0.50; P < 0.01) and apolipoprotein A-I (apo A-I: r = 0.72; P < 0.01). With improving metabolic control HDL2 lipid levels increased more than twofold and the compositional changes in HDL2 were reflected by an increased apo A-I:apo A-II ratio (P < 0.05) and a decreased triglyceride:apo A-I ratio (P < 0.05). Changes in HDL3 levels and composition were minor. The results of this study indicate that an increase in LCAT activity increases the concentration and changes the composition of HDL2 in type 1 diabetic patients with improved metabolic control. |
| Lecithin:cholesterol acyltransferase activity in patients with acute myocardial infarction and coronary heart disease Solajic-Bozicevic, N., A. Stavljenic, et al. (1991), Artery 18(6): 326-40. Abstract: Literature data suggest that identification of the conditions preventing lecithin:cholesterol acyltransferase (LCAT) to produce normal cholesterol esterification might be of utmost importance in the follow-up of atherosclerosis. Interrelationship between LCAT activity, and total cholesterol (TC), unesterified cholesterol (UC), esterified cholesterol (EC), low and high density lipoprotein cholesterol (LDL-C, HDL-C), triglycerides (TG), phospholipids (PL), free fatty acids (FFA), l-lactate (LAC), and electrolytes, i.e. zinc (Zn), calcium (Ca) and magnesium (Mg), was investigated in 60 patients with acute myocardial infarction (AMI), 30 patients with coronary heart disease (CHD) and 30 healthy control subjects. Results of the study revealed LCAT activity to be significantly decreased in atherosclerotic patients, with a significantly increased ratio of unesterified-esterified cholesterol (UC/EC), as compared to the control group of normal subjects. A decreased LCAT activity was accompanied by elevated values of phospholipids and LDL-C, a moderate increase in triglycerides, and a decreased quotient of HDL3/HDL2 cholesterol. Accordingly, a decreased activity of LCAT could with great certainty be considered a high-risk biochemical factor for atherosclerosis. |
| Lecithin:cholesterol acyltransferase deficiency increases atherosclerosis in the low density lipoprotein receptor and apolipoprotein E knockout mice Furbee, J. W., Jr., J. K. Sawyer, et al. (2002), J Biol Chem 277(5): 3511-9. Abstract: The purpose of the present study was to test the hypothesis that lecithin:cholesterol acyltransferase (LCAT) deficiency would accelerate atherosclerosis development in low density lipoprotein (LDL) receptor (LDLr-/-) and apoE (apoE-/-) knockout mice. After 16 weeks of atherogenic diet (0.1% cholesterol, 10% calories from palm oil) consumption, LDLr-/- LCAT-/- double knockout mice, compared with LDLr-/- mice, had similar plasma concentrations of free (FC), esterified (EC), and apoB lipoprotein cholesterol, increased plasma concentrations of phospholipid and triglyceride, decreased HDL cholesterol, and 2-fold more aortic FC (142 +/- 28 versus 61 +/- 20 mg/g protein) and EC (102 +/- 27 versus 61+/- 27 mg/g). ApoE-/- LCAT-/- mice fed the atherogenic diet, compared with apoE-/- mice, had higher concentrations of plasma FC, EC, apoB lipoprotein cholesterol, and phospholipid, and significantly more aortic FC (149 +/- 62 versus 109 +/- 33 mg/g) and EC (101 +/- 23 versus 69 +/- 20 mg/g) than did the apoE-/- mice. LCAT deficiency resulted in a 12-fold increase in the ratio of saturated + monounsaturated to polyunsaturated cholesteryl esters in apoB lipoproteins in LDLr-/- mice and a 3-fold increase in the apoE-/- mice compared with their counterparts with active LCAT. We conclude that LCAT deficiency in LDLr-/- and apoE-/- mice fed an atherogenic diet resulted in increased aortic cholesterol deposition, likely due to a reduction in plasma HDL, an increased saturation of cholesteryl esters in apoB lipoproteins and, in the apoE-/- background, an increased plasma concentration of apoB lipoproteins. |
| Lecithin:cholesterol acyltransferase overexpression generates hyperalpha-lipoproteinemia and a nonatherogenic lipoprotein pattern in transgenic rabbits Hoeg, J. M., B. L. Vaisman, et al. (1996), J Biol Chem 271(8): 4396-402. Abstract: Cholesterol esterification within plasma lipoprotein particles is catalyzed by lecithin:cholesterol acyltransferase (LCAT). The impact of the overexpression of this enzyme on plasma concentrations of the different plasma lipoproteins in an animal model expressing cholesteryl ester transfer protein was evaluated by generating rabbits expressing human LCAT. A 6.2-kilobase human genomic DNA construct was injected into the pronuclei of rabbit embryos. Of the 1002 embryos that were injected, 3 founder rabbits were characterized that expressed the human LCAT gene. As in mice and humans, the principal sites of mRNA expression in these rabbits is in the liver and brain, indicating that the regulatory elements required for tissue-specific expression among these species are similar. The alpha-LCAT activity correlated with the number of copies of LCAT that integrated into the rabbit DNA. Compared with controls, the high expressor LCAT-transgenic rabbits total and high density lipoprotein (HDL) cholesterol concentrations were increased 1.5-2.5-fold with a 3.1-fold increase in the plasma cholesterol esterification rate. Analysis of the plasma lipoproteins by fast protein liquid chromatography indicates that these changes reflected an increased concentration of apolipoprotein E-enriched, HDL1-sized particles, whereas atherogenic apolipoprotein B particles disappeared from the plasma. The concentrations of plasma HDL cholesterol were highly correlated with both human LCAT mass (r = 0.93; p = 0.001) and the log LCAT activity (r = 0.94; p < 0.001) in the transgenic rabbits. These results indicate that overexpression of LCAT in the presence of cholesteryl ester transfer protein leads to both hyperalpha-lipoproteinemia and reduced concentrations of atherogenic lipoproteins. |
| Lecithin:cholesterol acyltransferase reaction on cellular lipid released by free apolipoprotein-mediated efflux Czarnecka, H. and S. Yokoyama (1995), Biochemistry 34(13): 4385-92. Abstract: Lecithin:cholesterol acyltransferase (LCAT) reaction was studied in free apolipoprotein-mediated cellular lipid efflux from mouse peritoneal macrophages and human skin fibroblasts. When the cells were incubated with lipid-free human apolipoproteins (apo) A-I or A-II, pre-beta high density lipoprotein (HDL) particles were generated by removing cellular cholesterol and phospholipid. Cholesterol was esterified by LCAT in such particles generated with human apoA-I, but not in those with apoA-II. The reactivity of the apoA-I-pre-beta-HDL particles with LCAT was in the same order as that in human plasma HDL and in phosphatidylcholine/cholesterol unilamellar vesicles activated by apoA-I when compared on the rate of percent cholesterol esterification. However, cholesterol efflux mediated by apoA-I was not enhanced by active cholesterol esterification in the medium from either type of cells. Thus, it is unlikely the LCAT reaction on newly generated pre-beta-HDL directly causes further cellular cholesterol efflux. In control experiments, LCAT esterified cholesterol on human plasma HDL in the cell medium regardless of its origin, either HDL or cells. Cholesterol esterification on HDL was unable to enhance cellular cholesterol efflux significantly but reduced the influx of cholesterol from HDL to cell, resulting in the increase of net efflux of cellular cholesterol, in agreement with the results previously demonstrated. |
| Lecithin:cholesterol acyltransferase: role of N-linked glycosylation in enzyme function O, K., J. S. Hill, et al. (1993), Biochem J 294 (Pt 3): 879-84. Abstract: Lecithin:cholesterol acyltransferase (LCAT; phosphatidylcholine-sterol acyltransferase, EC 2.3.1.43) is a glycoprotein which is responsible for the formation of cholesteryl ester in plasma. The carbohydrate content has been estimated to be approx. 25% of the total LCAT mass, and four potential N-linked glycosylation sites have been predicted at residues 20, 84, 272 and 384 of the LCAT protein sequence. In the present study, we have examined which of these sites are utilized and how the N-glycosylation affects the secretion and function of the enzyme. Site-directed mutagenesis was performed to eliminate the glycosylation consensus sequence at each of the four potential sites, and the mutant proteins were expressed in COS cells. The amount of each mutant LCAT secreted was similar to that of the wild-type enzyme but the molecular mass was decreased by 3-4 kDa. The specific activity of each mutant LCAT was significantly different from the wild-type; however, the magnitude and direction of the change depended on the glycosylation site mutagenized. Loss of carbohydrate at position 20, 84 or 272 resulted in a decrease in the specific activity of the mutant enzymes by 18%, 82%, and 62% respectively. In contrast, the mutant protein without glycosylation at position 384 displayed a 2-fold increase in enzyme activity. In addition, a quadruple mutant was constructed such that all four potential glycosylation sites were eliminated. The amount of the unglycosylated LCAT secreted into the culture medium was less than 10% of the wild-type level and the specific activity of this enzyme was decreased to 5% of that of the wild type. The results demonstrate that all four potential N-glycosylation sites in LCAT are used and the presence of carbohydrate at each site has diverse effects on the enzyme activity. |
| Lecithin-cholesterol acyltransferase (LCAT) catalyzes transacylation of intact cholesteryl esters. Evidence for the partial reversal of the forward LCAT reaction Sorci-Thomas, M., J. Babiak, et al. (1990), J Biol Chem 265(5): 2665-70. Abstract: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the intravascular synthesis of lipoprotein cholesteryl esters by converting cholesterol and lecithin to cholesteryl ester and lysolecithin. LCAT is unique in that it catalyzes sequential reactions within a single polypeptide sequence, a phospholipase A2 reaction followed by a transacylation reaction. In this report we find that LCAT mediates a partial reverse reaction, the transacylation of lipoprotein cholesteryl oleate, in whole plasma and in a purified, reconstituted system. As a result of the reverse transacylation reaction, a linear accumulation of 3Hcholesterol occurred during incubations of plasma containing high density lipoprotein labeled with 3Hcholesteryl oleate. When high density lipoprotein labeled with cholesteryl 14Coleate was also included in the incubation the labeled fatty acyl moiety remained in the cholesteryl 14Coleate pool showing that the formation of labeled cholesterol did not result from hydrolysis of the doubly labeled cholesteryl esters. The rate of release of 3Hcholesterol was only about 10% of the forward rate of esterification of cholesterol using partially purified human LCAT and was approximately 7% in whole monkey plasma. Therefore, net production of cholesterol via the reverse LCAT reaction would not occur. 3HCholesterol production from 3Hcholesteryl oleate was almost completely inhibited by a final concentration of 1.4 mM 5,5'-dithiobis(nitrobenzoic acid) during incubation with either purified LCAT or whole plasma. Addition of excess lysolecithin to the incubation system did not result in the formation of 14Coleate-labeled lecithin, showing that the reverse reaction found here for LCAT was limited to the last step of the reaction. To explain these results we hypothesize that LCAT forms a 14Coleate enzyme thioester intermediate after its attack on the cholesteryl oleate molecule. Formation of this intermediate allows 3Hcholesterol to be liberated from the enzyme by exchange with unlabeled cholesterol of plasma lipoproteins. The liberated 3Hcholesterol thereby becomes available for reesterification by LCAT as indicated by its appearance as newly synthesized cholesteryl linoleate. |
| Lecithin-cholesterol acyltransferase activity in normocholesterolaemic and hypercholesterolaemic roosters: modulation by lipid apheresis Kostner, K. M., J. L. Smith, et al. (1997), Eur J Clin Invest 27(3): 212-8. Abstract: Lipid apheresis, a recently described procedure for the elimination of lipid but not apolipoproteins from plasma, was applied to normocholesterolaemic and hypercholesterolaemic roosters. Lipid apheresis resulted in an immediate reduction in plasma unesterified cholesterol concentration, which was sustained for 150 min. The reduction in unesterified cholesterol concentration was higher in the normocholesterolaemic animals than in the hypercholesterolaemic animals. Lipid apheresis induced changes in the ratio of plasma unesterified to total cholesterol in normocholesterolamic animals but not in hypercholesterolaemic animals. In hypercholesterolaemic animals, lecithin-cholesterol acyltransferase (LCAT) activity was not affected by lipid apheresis, whereas in normocholesterolaemic animals LCAT activity was acutely reduced for 150 min after lipid apheresis. Saturated LCAT kinetics occurred in the hypercholesterolaemic animals but not in the normocholesterolaemic animals. LCAT obeyed Michaelis-Menten kinetics. After lipid apheresis, there was a pool of unesterified cholesterol that was available as substrate for LCAT to a greater extent in hypercholesterolaemic animals than in normocholesterolaemic animals. These observations may have important implications for lipid apheresis as a treatment for atherosclerosis. |
| Lecithin-cholesterol acyltransferase. Assay of cholesterol esterification and phospholipase A2 activities Parks, J. S., A. K. Gebre, et al. (1999), Methods Mol Biol 109: 123-31. |
| Lecithin-cholesterol acyltransferase: effects of mutagenesis at N-linked oligosaccharide attachment sites on acyl acceptor specificity Francone, O. L., L. Evangelista, et al. (1993), Biochim Biophys Acta 1166(2-3): 301-4. Abstract: Site-directed mutagenesis was used to generate lecithin-cholesterol acyltransferase (LCAT) species in which individual attachment sites for N-linked oligosaccharide residues were replaced with residues that prevent the attachment of carbohydrate. Mutants at three of four sites retained significant acyltransferase activity, and phospholipase activity in the absence of cholesterol. Mutation at one site (asn272) converted LCAT to a phospholipase generating fatty acids not cholesteryl esters. |
| Lecithin-cholesterol acyltransferase: role in lipoprotein metabolism, reverse cholesterol transport and atherosclerosis Santamarina-Fojo, S., G. Lambert, et al. (2000), Curr Opin Lipidol 11(3): 267-75. Abstract: In the past several years significant advances have been made in our understanding of lecithin-cholesterol acyltransferase (LCAT) function. LCAT beneficially alters the plasma concentrations of apolipoprotein B-containing lipoproteins, as well as HDL. In addition, its proposed role in facilitating reverse cholesterol transport and modulating atherosclerosis has been demonstrated in vivo. Analysis of LCAT transgenic animals has established the importance of evaluating HDL function, as well as HDL plasma levels, to predict atherogenic risk. |
| Leisure-time physical activity and high-density lipoprotein cholesterol in a biracial community sample Macera, C. A., G. W. Heath, et al. (1993), Ethn Dis 3(2): 152-7. Abstract: The purpose of this analysis was to describe the association of leisure-time physical activity and high-density lipoprotein cholesterol levels among a large community sample of African-American and white men and women. Physical assessment of high-density lipoprotein cholesterol, weight, height, waist, and hip measurements were obtained for 3121 randomly selected community participants (969 white men, 1409 white women, 205 African-American men, and 538 African-American women). Leisure-time physical activity was assessed from responses to a standard series of questions about participation in various leisure-time activities. We found an inverse relationship between leisure-time activities and high-density lipoprotein cholesterol levels in African Americans, in contrast to a positive association observed in whites; however, these associations failed to reach statistical significance after controlling for age and body composition. These results confirm a strong association of body composition with high-density lipoprotein cholesterol and support continued interventions designed to reduce overall body weight, particularly upper body weight. The results further suggest that the relationships between some life-style factors and HDL levels may be different among minorities. |
| Leptin and HDL-cholesterol in non-diabetic normotensive subjects Marinari, G. M., N. Scopinaro, et al. (2001), Obes Surg 11(3): 252-3. Abstract: BACKGROUND: We investigated the relationships between body mass index (BMI), serum leptin and serum HDL-cholesterol. MATERIAL AND METHODS: A retrospective study was carried out in 80 patients who did not have type 2 diabetes mellitus and/or high blood pressure. RESULTS: Both serum leptin and HDL-cholesterol serum levels correlated with BMI (r = 0.616 and r = -0.269, respectively), but when the BMI values were kept constant no correlation was found between serum leptin and HDL-cholesterol both in simple and in multiple regression. CONCLUSION: The findings suggest that serum leptin concentration is completely independent of lipid metabolism. |
| Leptin and total cholesterol are predictors of weight gain in pre-pubertal children Byrnes, S. E., L. A. Baur, et al. (1999), Int J Obes Relat Metab Disord 23(2): 146-50. Abstract: OBJECTIVE: The aim of this study was to identify specifically which biochemical indices predict excessive weight gain over time in a cohort of pre-pubertal children. SUBJECTS: Fifty nine healthy pre-pubertal children (age: 6.3-9.8y). MEASUREMENTS: Children were defined anthropometrically and biochemically at baseline. Height and weight measurements were then repeated after six (n=52) and 12 months (n=37). RESULTS: Weight change after six months (defined by a change in body mass index (BMI) z-score from baseline) demonstrated no correlation with fasting plasma levels of leptin, insulin, insulin:glucose (IG) ratio, cholesterol, triglyceride or high density lipoprotein (HDL) cholesterol. However, after 12 months there was a significant negative correlation between BMI z-score change and initial plasma leptin (r=-0.35, P=0.048) and this relationship strengthened when adjusted for body fat (from bio-electrical impedance; r=-0.46, P=0.009). In addition, there was a significant positive relationship between plasma total cholesterol and BMI z score change (r=0.38, P=0.03) and this relationship remained unchanged when adjusted for body fat. No relationship was observed between weight change after 12 months and plasma levels of insulin, IG ratio, HDL cholesterol or triglyceride. CONCLUSION: Plasma leptin and total cholesterol were found to be predictive of weight gain over 12 months in a cohort of pre-pubertal children. These two potential predictors can be readily measured in clinical practice and these findings may represent a method of defining the 'at risk of obesity' state in childhood. |
| Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice Lundasen, T., W. Liao, et al. (2003), J Biol Chem 278(44): 43224-8. Abstract: Cholesterol elimination from the body involves reverse cholesterol transport from peripheral tissues in which the elimination of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol by the liver and subsequent biliary excretion as free cholesterol and bile acids are important. In situations of peripheral fat and cholesterol accumulation, such as obesity, these pathways may be overloaded, contributing to increased cholesterol deposition. Leptin has an important role in obesity, suppressing food intake and increasing energy expenditure. This hormone, which is absent in genetically obese ob/ob mice, is also thought to be involved in the coordination of lipid excretion pathways, although available data are somewhat inconsistent. We therefore studied the expression of the hepatic HDL receptor, scavenger receptor class B type I (SR-BI), and the LDL receptor as well as the rate-limiting enzyme in bile acid synthesis, cholesterol 7alpha-hydroxylase (Cyp7a1), in leptin-deficient ob/ob mice and their wild-type controls. In ob/ob mice, protein levels of both LDL receptor and SR-BI were reduced, whereas LDL receptor mRNA levels were increased and those of SR-BI were reduced, regardless of challenge with a 2% cholesterol diet. In ob/ob mice, the enzymatic activity and mRNA for Cyp7a1 were reduced, and the increase in response to dietary cholesterol was blunted. Upon short-term (2 days) treatment with leptin, a dose-dependent increase was seen in the SR-BI protein and mRNA, whereas the Cyp7a1 protein and mRNA were reduced. Our findings indicate that leptin is an important regulator of hepatic SR-BI expression and, thus, HDL cholesterol levels, whereas it does not stimulate Cyp7a1 and bile acid synthesis. |
| Leptin promotes biliary cholesterol elimination during weight loss in ob/ob mice by regulating the enterohepatic circulation of bile salts Hyogo, H., S. Roy, et al. (2002), J Biol Chem 277(37): 34117-24. Abstract: Leptin administration to obese C57BL/6J (ob/ob) mice results in weight loss by reducing body fat. Because adipose tissue is an important storage depot for cholesterol, we explored evidence that leptin-induced weight loss in ob/ob mice was accompanied by transport of cholesterol to the liver and its elimination via bile. Consistent with mobilization of stored cholesterol, cholesterol concentrations in adipose tissue remained unchanged during weight loss. Plasma cholesterol levels fell sharply, and microscopic analyses of gallbladder bile revealed cholesterol crystals as well as cholesterol gallstones. Surprisingly, leptin reduced biliary cholesterol secretion rates without affecting secretion rates of bile salts or phospholipids. Instead, cholesterol supersaturation of gallbladder bile was due to marked decreases in bile salt hydrophobicity and not to hypersecretion of biliary cholesterol per se, such as occurs in humans during weight loss. In addition to regulating bile salt composition, leptin treatment decreased bile salt pool size. The smaller, more hydrophilic bile salt pool was associated with substantial decreases in intestinal cholesterol absorption. Within the liver, leptin treatment reduced the activity of 3-hydroxy-3-methylglutaryl-CoA reductase, but it did not change activities of cholesterol 7alpha-hydroxylase or acyl-CoA:cholesterol acyltransferase. These data suggest that leptin regulates biliary lipid metabolism to promote efficient elimination of excess cholesterol stored in adipose tissue. Cholesterol gallstone formation during weight loss in ob/ob mice appears to represent a pathologic consequence of an adaptive response that prevents absorption of biliary and dietary cholesterol. |