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The absolute rate of cholesterol biosynthesis in monocyte-macrophages from normal and familial hypercholesterolaemic subjects.

ABSTRACT: The true rate of cholesterogenesis in cultured monocyte-macrophages was determined from the incorporation of [2-14C]acetate into cholesterol, using the desmosterol (cholesta-5,24-dien-3 beta-ol) that accumulated in the presence of the drug triparanol to estimate the specific radioactivity of the newly formed sterols. It was shown that this procedure could be successfully adapted for use with cultured monocytes despite the accumulation of other unidentified biosynthetic intermediates. In cells maintained in 20% (v/v) whole serum approx. 25% of the sterol carbon was derived from exogenous acetate. Cholesterol synthesis was as high in normal cells as in cells from homozygous familial hypercholesterolaemic (FH) subjects and accounted for 50% of the increase in cellular cholesterol. The addition of extra low-density lipoprotein (LDL) reduced cholesterol synthesis, apparently through a decrease in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). When incubated in lipoprotein-deficient serum some cells did not survive, but those that remained showed a normal increase in protein content; the amount of cellular protein and cholesterol in each well did not increase and cholesterol synthesis was reduced by over 80%. HMG-CoA reductase activity fell less dramatically and the proportion of sterol carbon derived from exogenous acetate increased, suggesting that the low rate of cholesterogenesis with lipoprotein-deficient serum was due to a shortage of substrate. The results indicate that under normal conditions monocyte-macrophages obtain cholesterol from endogenous synthesis rather than through receptor-mediated uptake of LDL, and that synthesis together with non-saturable uptake of LDL provides the majority of the cholesterol required to support growth.

SUBMITTER: Patel DD

PROVIDER: S-EPMC1153503 | biostudies-other | 1984 Apr

REPOSITORIES: biostudies-other

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Project description:Coronary heart disease (CHD) is one of the major causes of death and disability in industrialised countries, with elevated blood cholesterol an established risk factor. Total plasma cholesterol reduction in populations suffering from primary hypercholesterolemia may lower CHD incidence. This study investigated the cholesterol reducing capacity of Lactobacillus plantarum ECGC 13110402, a strain selected for its high bile salt hydrolase activity, in 49 normal to mildly hypercholesterolaemic adults. Primary efficacy outcomes included effect on blood lipids (total cholesterol (TC), low density lipoproteins (LDL-C), high density lipoproteins (HDL-C) and triacylgycerides (TAG), inflammatory biomarkers and occurrence/severity of gastrointestinal side effects to establish safety and tolerance of the intervention. Secondary outcomes included blood pressure, immune biomarkers, gut microbiota characterisation and metabonome changes. The study was run in a parallel, double blind, placebo controlled, randomised design in which the active group ingested 2x109 CFU encapsulated Lactobacillus plantarum ECGC 13110402 twice daily. Daily ingestion of the active treatment resulted in a statistically significant reduction in LDL-C in volunteers with baseline TC<5mM during the 0-12 week period (13.9%, P = 0.030), a significant reduction in TC in volunteers with baseline TC?6mM in the 0-6 week period (37.6%, P = 0.045), a significant decrease in TAG (53.9% P = 0.030) and an increase in HDL-C (14.7%, P = 0.007) in the over 60 years population in the 6-12 week period. A statistically significant reduction in systolic blood pressure was also observed across the active study group in the 6-12-week period (6.6%, P = 0.003). No impact on gastrointestinal function and side effects was observed during the study. Similar to blood and urine metabonomic analyses, faecal metagenomics did not reveal significant changes upon active or placebo intake. The results of this study suggest that Lactobacillus plantarum ECGC 13110402 is a well-tolerated, natural probiotic, that may be used as an alternative or supplement to existing treatments to reduce cardiovascular risk.Clinical trials.gov NCT03263104.

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The absolute rate of cholesterol biosynthesis in monocyte-macrophages from normal and familial hypercholesterolaemic subjects.

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