LCAT
Phosphatidylcholine-sterol acyltransferase precursor (EC 2.3.1.43) (1-alkyl-2-acetylglycerophosphocholine esterase) (EC 3.1.1.47) (Lecithin-cholesterol acyltransferase) (Phospholipid-cholesterol acyltransferase) (Platelet-activating factor acetylhydrolase) (PAF acetylhydrolase)
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Dietary sphingomyelin (SM) is hydrolyzed by intestinal alkaline sphingomyelinase and neutral ceramidase to sphingosine, which is absorbed and converted to palmitic acid and acylated into chylomicron triglycerides (TGs). SM digestion is slow and is affected by luminal factors such as bile salt, cholesterol, and other lipids. In the gut, SM and its metabolites may influence TG hydrolysis, cholesterol absorption, lipoprotein formation, and mucosal growth. SM accounts for approximately 20% of the phospholipids in human plasma lipoproteins, of which two-thirds are in LDL and VLDL. It is secreted in chylomicrons and VLDL and transferred into HDL via the ABCA1 transporter. Plasma SM increases after periods of large lipid loads, during suckling, and in type II hypercholesterolemia, cholesterol-fed animals, and apolipoprotein E-deficient mice. SM is thus an important amphiphilic component when plasma lipoprotein pools expand in response to large lipid loads or metabolic abnormalities. It inhibits lipoprotein lipase and LCAT as well as the interaction of lipoproteins with receptors and counteracts LDL oxidation. The turnover of plasma SM is greater than can be accounted for by the turnover of LDL and HDL particles. Some SM must be degraded via receptor-mediated catabolism of chylomicron and VLDL remnants and by scavenger receptor class B type I receptor-mediated transfer into cells.
MeSH Terms
- Aging
- Amidohydrolases
- Animals
- Animals, Newborn
- Apolipoproteins E
- Biological Transport, Active
- Cell Differentiation
- Cell Proliferation
- Ceramidases
- Cholesterol, Dietary
- Chylomicrons
- Dietary Fats
- Humans
- In Vitro Techniques
- Infant, Newborn
- Intestinal Absorption
- Lipoproteins
- Models, Biological
- Neutral Ceramidase
- Sphingomyelin Phosphodiesterase
- Sphingomyelins
- Triglycerides
Various aspects of lipid metabolism were compared in Fisher 344 (F) and Sprague-Dawley (SD) rats aged 2, 6, 12, 18 and 24 months. The analyses included free and total cholesterol of serum and liver, LCAT, hepatic HMG-CoA reductase, cholesterol 7 alpha-hydroxylase, fatty acid synthetase, acetyl CoA carboxylase and cholesterol synthesis from acetate or mevalonate. The body weight of SD rats increases with age whereas that of F rats plateaus at 9-12 months. Liver and aorta cholesterol levels were comparable for the 2 strains. Serum cholesterol varied but was usually lower in F rats. HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities were not significantly different. Cholesterol synthesis from acetate was significantly higher only in 2-month-old F rats; synthesis from mevalonate was similar at each level. Acetyl CoA carboxylase and fatty acid synthetase activity were generally higher in F rats at every age level. The major difference between F and SD rats is in their pattern of weight gain with age. Differences in lipid metabolism are most marked between the young (2-month) rats.
MeSH Terms
- Aging
- Animals
- Body Weight
- Cholesterol
- Cholesterol 7-alpha-Hydroxylase
- Hydroxymethylglutaryl CoA Reductases
- Lipid Metabolism
- Liver
- Male
- Phosphatidylcholine-Sterol O-Acyltransferase
- Rats
- Species Specificity
Plasma unesterified cholesterol is converted to cholesteryl ester by the enzyme lecithin-cholesterol acyltransferase (LCAT). Plasma levels of LCAT were measured by a sensitive double antibody radioimmunoassay in a sample from an adult employee population, ages 20-59 years, in the Pacific Northwest. After adjusting for differences in relative body mass, women had significantly higher LCAT levels (5.90 /- 1.06, n = 154) than men (5.49 /- 0.89, n = 83). For ages 20-59 years, LCAT levels showed a slight association with age: r = 0.13 for men and 0.29 for women. LCAT was positively correlated with relative body mass, total cholesterol, and LDL cholesterol. Men who smoked cigarettes had significantly lower LCAT mass than men who did not smoke cigarettes. No statistical differences in mean LCAT values were found between drinkers and nondrinkers. The 5th percentile LCAT value was 4.3 micrograms/ml for both men and women not using hormones. The 95th percentile value was 7.3 micrograms/ml for men and 7.8 micrograms/ml for women regardless of hormone use. Subjects phenotypically LCAT-deficient by clinical criteria and by the absence or near absence of LCAT activity had levels of LCAT mass well below the reference values: 0.73 /- 0.70, range 0.10 micrograms/ml to 2.65 micrograms/ml, n = 20. Parents or children of LCAT-deficient subjects, i.e., obligate heterozygotes for familial LCAT deficiency, had reduced levels: 3.59 /- 0.69, range 2.59-4.61 micrograms/ml, n = 19.
MeSH Terms
- Adult
- Aged
- Aging
- Alcohol Drinking
- Body Weight
- Cholesterol
- Contraceptives, Oral
- Estrogens
- Female
- Health Surveys
- Humans
- Hypolipoproteinemias
- Japan
- Lecithin Cholesterol Acyltransferase Deficiency
- Male
- Middle Aged
- Norway
- Phosphatidylcholine-Sterol O-Acyltransferase
- Population
- Reference Values
- Smoking
- Triglycerides
- Washington
Plasma lecithin:cholesterol acyltransferase (LCAT) has been measured by an enzymatic method. We did not observe any significant sex variations, but age variations were found. In females, LCAT activities are stable up to 40 years (60 mumol . 1.1 . h-1 at the 50th centile). Also, from 50 years the median increased progressively to 76 mumol . 1-1 . h-1. In males, the activity increased from 52 to 71 mumol . 1-1 . h-1 at the 50th centile in two age groups (15-20 years and 50 years). The effect of some xenobiotics on LCAT activity was studied. We observed an increase in activity of 33% in males when the daily alcoholic beverage consumption ranged from 0 to more than 0.5 litre of wine or beer. LCAT activity increased in children who were treated with hypolipidemic drugs (fenofibrate, Lipanthyl). In boys, the mean enzyme activity increased to 35% (p less than 0.05). The increase was greater in girls (75%, p less than 0.01). Treatment with anticonvulsant drugs gave a decrease in LCAT activity of 32-46%.
MeSH Terms
- Adolescent
- Adult
- Aging
- Alcohol Drinking
- Anticonvulsants
- Child
- Child, Preschool
- Female
- Fenofibrate
- Humans
- Hypolipidemic Agents
- Male
- Middle Aged
- Phosphatidylcholine-Sterol O-Acyltransferase
- Quality Control
- Reference Values
- Sex Factors
Plasma cholesterol and triglyceride levels and selected molecular species of plasma cholesteryl esters and triglycerides were determined in 6-, 12-, 15-, 18-, 21-, and 24-month-old Fischer-344 rats. Lecithin:cholesterol acyltransferase (LCAT) activity was also determined using two independent methods utilizing endogenous and exogenous substrates. Plasma cholesterol levels increased up to 18 months of age and then plateaued. Of the plasma triglyceride molecular species investigated (C50, C52, C54 and C56), only the levels of C52 increased linearly with age. The concentration of other triglyceride molecular species did not change with age. The fractional rate of plasma cholesterol esterification showed a decreasing trend with age, whereas, the net cholesterol esterification rate showed a gradual age related increase. However, this latter parameter remained unchanged with age when the data were normalized for body weight. The cholesterol esterification rates measured using an exogenous substrate (estimating LCAT enzyme levels) showed essentially no change with age. These data indicate that changes in the levels and/or composition of lipoprotein substrate(s) for LCAT are likely causes of the observed age-related changes in the fractional rate of plasma cholesterol esterification. The net esterification rate of plasma cholesterol was significantly correlated with the plasma triglyceride levels when the animals for all age groups were treated as one experimental group.
MeSH Terms
- Aging
- Animals
- Cholesterol
- Cholesterol Esters
- Male
- Phosphatidylcholine-Sterol O-Acyltransferase
- Rats
- Rats, Inbred F344
- Substrate Specificity
- Triglycerides
The association between serum lecithin: cholesterol acyltransferase (LCAT) activity and demographic and environmental factors, and the correlation of LCAT activity with serum lipids and lipoproteins were studied in a representative series of 1071 9-24-year-old subjects from East and West Finland. LCAT activity was determined by a method involving the use of exogenous substrate. Males had higher LCAT activity than females and subjects from East Finland had significantly higher activity than those from West Finland. LCAT activity tended to be lowest shortly after puberty. Women using oral contraceptives had significantly lower LCAT activity than women not using them. Serum LCAT activity was not associated with body mass index, physical activity index or smoking. Serum LCAT activity correlated positively with most serum lipid and lipoprotein variables. The highest correlation coefficients were found between LCAT activity and total cholesterol. LCAT activity correlated positively with the change in serum total cholesterol which had occurred during the preceding 3 and 6 years in men. Our results suggest that sex hormonal factors are associated with serum LCAT activity. The results are also in accordance with the idea that activity of LCAT increases in response to enhanced demands for cholesterol esterification in plasma.
MeSH Terms
- Adolescent
- Adult
- Aging
- Child
- Child, Preschool
- Cholesterol, HDL
- Contraceptives, Oral
- Coronary Disease
- Female
- Finland
- Humans
- Lipoproteins
- Male
- Phosphatidylcholine-Sterol O-Acyltransferase
- Sex Characteristics
- Smoking
Lecithin:cholesterol acyltransferase (LCAT) catalyzes the esterification of cholesterol in high density lipoproteins, thereby facilitating transport of excess cholesterol from peripheral tissues to liver. We report here studies of the developmental, dietary, and genetic control of LCAT gene expression. In adult male Sprague-Dawley rats fed a standard chow diet LCAT mRNA was most abundant in liver, a major source of the plasma enzyme, but appreciable levels were also present in brain and testes. Since both brain and testes are isolated from blood by tight cellular barriers, undoubtedly greatly reducing the level of plasma-derived LCAT in cerebrospinal fluid and testes, the production of LCAT in these tissues may be important for removal of excess cholesterol. Noteworthy changes in the expression of LCAT mRNA were observed during development of both rodents and humans. On the other hand, LCAT mRNA levels were relatively resistant to dietary challenge or to drugs affecting cholesterol metabolism. Since human epidemiological studies have suggested an association between LCAT levels and variations of high density lipoprotein cholesterol, we examined LCAT gene polymorphisms in a mouse animal model. Mapping of the LCAT gene (Lcat) to mouse Chromosome 8 within 2 centimorgans of the Es-2 locus indicates that it does not correspond to any previously mapped loci affecting high density lipoprotein phenotypes in the mouse.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- Brain
- Chromosome Mapping
- Chromosomes, Human, Pair 16
- Cloning, Molecular
- Diet
- Embryonic and Fetal Development
- Female
- Gene Expression
- Gene Expression Regulation, Enzymologic
- Gene Library
- Genes
- Humans
- Liver
- Male
- Mice
- Mice, Inbred Strains
- Molecular Sequence Data
- Organ Specificity
- Phosphatidylcholine-Sterol O-Acyltransferase
- RNA, Messenger
- Sequence Homology, Nucleic Acid
- Testis
- Transcription, Genetic
In two feeding experiments immature (180 g) and mature rats (370 g) were fed a semi-purified diet containing 20% of a protein source (casein, wheat gluten, soybean or potato protein) for 4 wk. Food supply was restricted to 15 g daily. As compared to casein, plant proteins induced significantly lower concentrations of plasma total cholesterol and high density lipoprotein (HDL) cholesterol. The plasma cholesterol increase associated with aging was not prevented by consumption of casein, soybean or potato protein, but wheat gluten seemed to be effective. Lecithin-cholesterol acyltransferase (LCAT) activity was not significantly different in rats of the same age fed different plant proteins, whereas the esterification rate was lower in rats fed casein. With aging the LCAT activity generally decreased. As compared to the casein groups, the rats fed plant proteins showed higher excretion of fecal neutral and acidic steroids. Among the groups fed plant proteins, the fecal output of steroids was variable. Significantly negative correlations were found between fecal total sterol excretion and plasma total cholesterol or HDL cholesterol, respectively. Plant proteins showed a faster migration rate in the stomach, whereas their migration and absorption were slower in the first half of the small intestine. A relation between nonabsorbed nitrogen-containing substances and sterol excretion was hypothesized.
MeSH Terms
- Aging
- Amino Acids
- Animals
- Bile Acids and Salts
- Caseins
- Cholesterol
- Cholesterol, HDL
- Cholesterol, LDL
- Dietary Proteins
- Feces
- Glutens
- Male
- Phosphatidylcholine-Sterol O-Acyltransferase
- Plant Proteins
- Plant Proteins, Dietary
- Rats
- Rats, Inbred Strains
- Solanum tuberosum
- Soybean Proteins
- Sterols
The activity of the enzyme lecithin:cholesterol acyltransferase (LCAT) and the properties of its lipoprotein substrates have been investigated in 6- and 19-month-old Fischer-344 rats. These studies were carried out to determine the nature of the relationship between the observed hypercholesterolemia and the age-related decrease in the fractional rate of lipoprotein cholesterol esterification. The distribution of LCAT activity of plasma fractions was determined following gel chromatography and ultracentrifugation respectively. LCAT activity was found to be associated with the high density lipoprotein (HDL) fraction when rat plasma was passed through a Bio-Gel A-5 M column. Upon density gradient ultracentrifugation for 24 h it was found associated with HDL fraction; d = 1.125-1.21 g/ml. However, following prolonged ultracentrifugation (40 h), the majority of the LCAT activity was displaced into the lipoprotein-free infranatant (d greater than 1.225 g/ml). The dissociation of LCAT from its complex with HDL occurred to a smaller extent in aged rat plasma than in young rat plasma. Substrate specificity studies indicated that HDL was a considerably better substrate for LCAT than very low density lipoproteins (VLDL) in both young and aged rats. In addition, HDL from young rats was a better substrate for LCAT than the HDL from aged rats. Incubation experiments followed by the isolation of lipoproteins and the subsequent analyses of their cholesterol contents revealed that the age-related hypercholesterolemia was mainly due to an increase in the cholesterol carried by lipoprotein fractions d = 1.025 -1.07 g/ml (LDL HDL1). These and other low density lipoproteins (d less than 1.025 g/ml) were poor substrates for LCAT. However, these lipoproteins could provide free cholesterol for esterification by first transferring it to HDL (d = 1.07-1.21). The HDL isolated from the plasma of aged rats was enriched with apolipoprotein (apo) E and these lipoprotein particles were found to be inferior substrates for LCAT. These data suggest that the decreased fractional rate of esterification observed in aged rats is due to the slower utilization of the HDL lipid substrate pool by the enzyme LCAT as a result of the accumulation of unfavorable substrates (compositionally altered HDL particles) for the LCAT reaction.
MeSH Terms
- Aging
- Animals
- Cholesterol
- Cholesterol Esters
- Lipoproteins
- Lipoproteins, HDL
- Lipoproteins, VLDL
- Male
- Phosphatidylcholine-Sterol O-Acyltransferase
- Rats
- Rats, Inbred F344
- Substrate Specificity
The induction of hepatic lipoprotein (apo B/E) have been investigated in Fischer-344 rats. These studies were aimed to determine the mechanism underlying the previously observed (Lee et al., Mech. Ageing Dev., 61 (1991) 85-98) hypercholesterolemia and the age-related decrease in the fractional rate of endogenous cholesterol esterification. Young (5 months) and aged (22 months) male Fischer-344 rats were treated with pharmacological doses (5 mg/kg per day) of ethinyl estradiol (EE) for 7 days. Reduction of plasma cholesterol (57% in young vs 47% in aged rats) and high density lipoprotein cholesterol (64% in young vs 63% in aged rats) occurred in both groups upon EE treatment. Initial low density lipoprotein levels were very low in the plasma of young rats and consequently were not affected by EE treatment. However, in aged rats, the low density lipoprotein levels were much higher initially and were markedly reduced by EE treatment. (18.0 vs 10.0 mg/dl). Very low density lipoproteins were about the same initially but increased in aged rats and decreased in young rats upon EE treatment. Both the lecithin:cholesterol acyltransferase (LCAT) activity (as determined with a proteoliposome substrate) and the fractional rate (FR) of the endogenous cholesterol esterification decreased in treated animals compared to controls. However, the differences in the FR of the endogenous cholesterol esterification between young and aged rats (observed before treatment) were nearly abolished upon treatment. These data suggest that the previously observed age related decrease in the FR of endogenous cholesterol esterification is due to the accumulation of apolipoprotein E-rich (apo E) lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Aging
- Animals
- Apolipoproteins E
- Cholesterol Esters
- Ethinyl Estradiol
- Lipoproteins
- Lipoproteins, HDL
- Liver
- Male
- Organ Size
- Phosphatidylcholine-Sterol O-Acyltransferase
- Rats
- Rats, Inbred F344