Cholesterol Metabolism In Human Cells Research Articles

Role of ANXA1, IL15, PERK, INSIG1 genes and endoplasmic reticulum stress in foam cell formation

Background and Aims: Endoplasmic reticulum (ER) stress disturbs cholesterol metabolism in human cells by impairing cholesterol efflux, influx, and synthesis. Cholesterol loading of human monocyte-derived macrophages (MDM) by LDL resulted in increased ANXA1, CXCL8, IL-15, and PERK mRNA expressions. Incubation of MDM with HDL, in turn, led to increased INSIG1 mRNA expression. In this study, our aim was to evaluate the role of ANXA1, IL15, PERK, CXCL8, INSIG1 genes in cholesterol metabolism.

Osteopontin levels are associated with cholesterol synthesis markers in mildly hypercholesterolaemic patients

Objective — Atherosclerotic lesions are characterized by an accumulation of inflammatory cells and lipids. Osteopontin (OPN) is a cell-binding phosphoprotein, and it seems to promote the development of atherosclerosis.The purpose of our study was to find out whether plasma levels of OPN are associated with cholesterol metabolites in plasma or tissues.Methods and results — Forty-three normal or mildly hypercholesterolaemic subjects, aged 31 to 69, were studied.The plasma level of OPN correlated negatively with muscle lathosterol (r = –0.52, P < 0.0001) and with the muscle lathosterol to muscle cholesterol ratio (r = –0.48, P=0.001). Lathosterol concentrations in muscle (P=0.003) and in relation to cholesterol (P=0.005) were also significantly different among the OPN tertiles. OPN correlated negatively and significantly with muscle lathosterol in men (r = –0.58, P=0.001, n=29) but not in women (r = –0.21, P =0.48, n=14). Correspondingly, it also correlated negatively and significantly with the muscle lathosterol to muscle cholesterol ratio (r = –0.60, P=0.001) in men but not in women (r = –0.13, P=0.65). Plasma levels of OPN had a non-significant inverse correlation with plasma lathosterol and the plasma lathosterol to plasma cholesterol ratio. Plasma OPN concentrations were not related to plant sterols, cholesterol and 27-hydroxycholesterol.Conclusions — Tissue markers of cholesterol synthesis were related to plasma OPN, particularly in men.This suggests that there is interplay between OPN and cholesterol metabolism in human cells.

Melatonin Inhibits LDL Receptor Activity and Cholesterol-Synthesis in Freshly Isolated Human Mononuclear Leukocytes

There is some indirect evidence that the pineal hormone melatonin can suppress plasma levels of cholesterol in hypercholesterolemic rats. We have examined the effects of the hormone on cellular cholesterol metabolism in freshly isolated human mononuclear leukocytes. Incubation of cells for up to 20 h in a lipid-free medium resulted in an increase in the rate of cholesterol synthesis from [14C]acetate and the high affinity accumulation and degradation of [125I]labeled low density lipoprotein (LDL). Addition of melatonin in increasing concentrations to the incubation medium at zero time inhibited cholesterol synthesis and the specific accumulation and degradation of [125I]labeled LDL; at a concentration of 100 μM, the inhibitions were 38 %, 42 %, and 48 %, respectively. Similar results were obtained using [14C]mevalonate as precursor. Fatty acid synthesis was not altered under these conditions. In contrast to cholesterol the synthesis of the first cyclic compound lanosterol was not affected by the pineal hormone. These results implicate that melatonin inhibits this pathway between lanosterol and cholesterol. The action of melatonin on LDL receptor activity appeared to be mediated by a decrease in the number of LDL receptors and not by a change in binding affinity. Pharmacological characterization of the potential melatonin receptor site using several analogs hire tryptamine, 5-hydroxytryptamine, N-acetyl-5-hydroxtryptamine, 5-methoxytryptamine, and 6-chloromelatonin indicated that the 5-methoxy group is indispensible for the hormone action on cholesterol synthesis. The data provide evidence that melatonin can modulate cholesterol metabolism in human cells.

Lipoprotein receptors and the genetic control of cholesterol metabolism in cultured human cells

Biochemical analysis of cultured fibroblasts obtained from human subjects with the autosomal dominant disorder familial hypercholesterolemia has led to the identification of a hitherto unrecognized cell-surface receptor for serum lipoproteins. This receptor plays a critical role in the physiologic regulation of cholesterol metabolism in human cells, and its absence leads to elevation of serum-cholesterol levels and severe atheroslerosis.

Use of mutant fibroblasts in the analysis of the regulation of cholesterol metabolism in human cells

Analysis of mutant human fibroblasts deficient in a cell surface receptor for low density lipoproteins (LDL) has led to the delineation of an important, hitherto unrecognized, regulatory process for cholesterol metabolism. On normal cells, binding of LDL to this receptor regulates cholesterol metabolism by two mechanisms: (a) suppression of cholesterol synthesis and (b) facilitation of the rate of proteolytic degradation of the lipoprotein. In cells from homozygotes with the autosomal dominant disorder Familial Hypercholesterolemia, a nearly total reduction in LDL receptors results in two secondary abnormalities: (a) overproduction of cholesterol due to an inability of LDL to suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis, and (b) impairment in the rate of proteolytic degradation of LDL. Cells from heterozygotes possess about 50 per cent of the normal number of LDL recpetors; this leads to a concentration-dependent defect in regulation, so that attainment of rates of cholesterol synthesis and LDL degradation equal to that in normal cells requires a two to three-fold higher concentration of extracellular LDL in the heterozygote. The identification of this genetic regulatory defect in fibroblasts of heterozygotes with Familial Hypercholesterolemia makes available an in vitro system for studying the molecular mechanism by which a dominant mutation affects gene expression in mammalian cells.