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Biomedical subjects

A G Lacko

Publications and source records attributed to A G Lacko.

15 recordsLinked to original sources
PubMed1992

Decreased lecithin:cholesterol acyltransferase activity in the plasma of hypercholesterolemic pigs.

Lecithin:cholesterol acyltransferase (LCAT) activity levels were determined, as function of plasma total cholesterol (TC) in 13 normocholesterolemic (TC less than 85 mg/dL) and in 28 hypercholesterolemic (TC greater than 98 mg/dL) pigs. The normocholesterolemic group consisted of pigs that carried apo-B allelic genes other than Lpb5 and or Lpb8. The hypercholesterolemic group consisted of Lpb5/x and Lpb5/8 heterozygous and Lpb5/5 homozygous animals. The data reported in this study show that the LCAT activity in the plasma of hypercholesterolemic (HC) pigs (79 +/- 43 units) was significantly lower (p less than 0.0005) compared to the normocholesterolemic controls (175 +/- 45 units). Furthermore, LCAT activity was positively correlated with TC in the normocholesterolemic group (r = +0.54; p less than 0.05), whereas it was negatively correlated with TC in the hypercholesterolemic group (r = -0.73; p less than 0.001). Additional data obtained from incubation experiments suggest that the lower LCAT activity in hypercholesterolemic pigs may be due, at least in part, to inhibition of LCAT activity by components found in the lipoprotein-deficient fractions of the plasma of hypercholesterolemic pigs.

Animals↗
PubMed1992

Effect of ethinyl estradiol treatment on lipoproteins and LCAT activity in aged rats.

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)

Aging↗
PubMed1992

The efficacy of gemfibrozil therapy for raising high density lipoprotein levels.

Thirty subjects, 5 normotriglyceridemic (NTG) with low HDL cholesterol (HDL-C < 35 mg/dl) and 25 hypertriglyceridemic (HTG) with low and high HDL-C (HDL-C > 35 mg/dl) were selected fo this study. They were treated with gemfibrozil (600 mg BID) for 12 weeks. In both groups, gemfibrozil significantly reduced serum TG levels (p < 0.005), yet HDL-C increased significantly only in HTG patients (p < 0.005). The changes in HDL-C levels were highly variable (-40 to 50%) and appeared to be dependent on the levels of serum TG achieved during treatment. Based on post-treatment serum TG, the HTG patients were divided into 2 groups. Group 1 with serum TG of < 100 mg/dL and Group 2 with serum TG levels > 100 mg/dl. Significant post treatment increases in HDL-C were seen only in Group 1 (p < 0.005). The two groups had similar pretreatment serum TG and HDL-C levels but the LDL-C was significantly higher in Group 1 (p < 0.025). Pretreatment serum LDL-C also correlated positively with the increases in HDL-C during treatment (r = 0.51, p < 0.01, n = 25). Consequently, the patients were divided into three groups based on their initial serum LDL-C levels (Group 1: LDL-C < 130 mg/dl. Group 2: LDL-C, 130-159 mg/dl and Group 3: LDL-C > 160 mg/dl). The HDL-C levels increased significantly upon treatment only in Group 3. Pretreatment levels of serum TG and HDL-C were not significantly different among the three groups. Initial body weight (r = -0.43 p < 0.025, n = 30) and percent change in body weight during treatment (r = -0.47, p < 0.025, n = 30) correlated negatively with the percent reduction in serum TG. The change in body weight also showed significant negative correlation with the changes in HDL cholesterol (r = -0.48, p < 0.25, n = 30). We conclude that gemfibrozil is most effective in reducing serum triglycerides, LDL-C and increasing serum HDL-cholesterol in HTG patients who also have comparatively high initial LDL cholesterol levels (Fredrickson's type IIb phenotype). For effective improvement of HDL-cholesterol in most HTG patients, serum TG levels need to be lowered below 100 mg/dl. Furthermore, the benefit of gemfibrozil therapy may be significantly enhanced by weight loss during treatment.

Adult↗
PubMed1992

Physiologic role and clinical significance of reverse cholesterol transport.

Low levels of high-density lipoproteins have been consistently shown to be a major risk factor for coronary heart disease. However, the precise role of HDL in the prevention or reversal of atherosclerosis (or both) is unknown. It has been proposed that HDL functions jointly with the enzyme lecithin:cholesterol acyltransferase and the cholesteryl ester transfer protein to facilitate the movement of cholesterol from tissues to the liver. This mechanism--referred to as reverse cholesterol transport--has been shown to be an important physiologic mechanism. However, its clinical significance, though intriguing, is unclear. This article reviews recent advances concerning the components of reverse cholesterol transport and evaluates their potential significance in the early diagnosis and treatment of atherosclerosis.

Arteriosclerosis↗
PubMed1991

Age related changes in the lipoprotein substrates for the esterification of plasma cholesterol in rats.

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.

Aging↗
PubMed1990

International Symposium on Reverse Cholesterol Transport. Report on a meeting.

The purpose of this symposium was to provide a forum for the reporting of recent findings and the exchange of ideas concerning reverse cholesterol transport, an area of intense interest and some controversy. Data from epidemiological studies have consistently shown that elevated levels of high density lipoproteins (HDL) are an index of increased protection against coronary heart disease. However, the mechanism whereby HDL is involved in the prevention and/or reversal of atherosclerosis is unknown. According to one of the hypotheses, HDL acts as the primary acceptor of unesterified cholesterol from cells and functions jointly with the enzyme lecithin:cholesterol acyltransferase (LCAT) and the cholesteryl ester transfer protein (CETP) to facilitate the movement of cholesterol from peripheral tissues to the plasma and ultimately to the liver. Although this mechanism as originally proposed by Glomset is an essential physiological mechanism, the clinical significance of this hypothesis remains unsubstantiated. Key elements of knowledge are lacking that would allow the linking of cholesterol efflux from cells and tissues with specific events in HDL metabolism, particularly those that are relevant to the prevention and/or reversal of atherosclerosis. Because of the intricate nature of the interaction between the components of reverse cholesterol transport, a conference involving the leading investigators of the field, where extensive discussion of the findings and ideas is allowed, appeared highly desirable. Indeed, from the distance of nearly 4 months, feedback from the participants indicates that the meeting was highly successful and the organizers feel that all the projected goals of the symposium were accomplished.

Biological Transport↗
PubMed1989

Relationship between cholesteryl ester transfer activity and high density lipoprotein composition in hyperlipidemic patients.

Cholesteryl ester transfer from solid-phase bound HDL to endogenous plasma HDL or VLDL/LDL was determined in 50 patients with primary disorders of lipid metabolism and 27 normolipidemic subjects. Transfer to the plasma HDL pool was significantly reduced in familial hypercholesterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia and dysbetalipoproteinemia. Subfractionation of HDL revealed that the lipid transfer to HDL3 was significantly reduced in all patient groups while transfer to HDL2 was increased in those with dysbetalipoproteinemia and familial hypertriglyceridemia. Transfer to LDL and VLDL was increased only in patients with dysbetalipoproteinemia and hypoalphalipoproteinemia. Reduced transfer to HDL occurred in samples with altered HDL composition; particularly where HDL-triglyceride was significantly increased and HDL-cholesteryl esters were reduced. Transfer of cholesteryl ester to HDL3 was significantly decreased in patients with vascular disease. These findings indicate that impaired interaction of cholesteryl ester transfer protein with the HDL3 pool may contribute to the risk of coronary heart disease in patients with specific plasma lipid abnormalities.

Cholesterol Esters↗
PubMed1989

Studies on the structure of lecithin:cholesterol acyltransferase (LACT)--comparisons of the active site region and secondary structure of the human and the porcine enzymes.

1. Chemical modification of essential serine, histidine and cysteine residues of porcine LCAT were accompanied by loss of enzymatic activity. 2. Modification of cysteine with DTNB inactivated the enzyme which could not be reactivated by KCN suggesting direct involvement of the cysteine residue(s) in catalysis. 3. About half of the primary structure of the porcine enzyme was determined. 4. Respective regions of the human and porcine LCAT are highly homologous; especially, the amino-terminus and the region surrounding the DFP-labeled serine residues. 5. The observed primary structure differences represent amino acid substitutions that are projected to induce significant changes in secondary structure.

Amino Acid Sequence↗
PubMed1978

Serum cholesterol esterification in hyperthyroidism and hypothyroidism.

The rate of serum cholesterol esterification was measured in twenty healthy subjects and compared to similar data obtained with seventeen hyperthyroid and ten hypothyroid subjects. No significant differences were noted in the rate of cholesterol esterification while differences in the fractional rates were highly significant (p less than 0.001); the hyperthyroid group being higher and the hypothyroid group lower than normal. There were no clear trends observed in the changes of the rate of cholesterol esterification upon therapy. However, the fractional rates always increased when hypothyroid patients became euthyroid and always decreased in hyperthyroid patients as the result of therapy.

Cholesterol↗
PubMed1976

On the interpretation and potential diagnostic value of the measurements related to lecithin:cholesterol acyltransferase activity.

At least one reliable method is available for measuring LCAT activity in human subjects(25), and this assay may help to probe even subtle changes in plasma lipids and lipoproteins. Since plasma lipids and lipoproteins are known to be present in abnormal amounts in a large number of metabolic diseases, the method of measuring the rate of cholesterol esterification in plasma could assume a substantial role in the diagnosis and (or) monitoring of treatment of pathologic states.

Acyltransferases↗