A Phytosterolemic Mixture of Sterols Inhibits Cholesterol Synthesis, Esterification, and Low-Density Lipoprotein Receptor mRNA Abundance in HepG2 Cells.

HepG2 cells were incubated with a 16.5:1.7:1 ratio of cholesterol:sitosterol:campesterol (CSC), a ratio of the major sterols observed in the plasma of phytosterolemia patients, or with cholesterol alone in combination with [ C]acetate for 24 h and the radioactivity incorporated into lipids determined.

Progress and perspectives in plant sterol and plant stanol research.

Current evidence indicates that foods with added plant sterols or stanols can lower serum levels of low-density lipoprotein cholesterol. This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Participants discussed issues including, but not limited to, the health benefits of plant sterols and stanols beyond cholesterol lowering, the role of plant sterols and stanols as adjuncts to diet and drugs, and the challenges involved in measuring plant sterols and stanols in biological samples.

The natural history of phytosterolemia: Observations on its homeostasis.

Background And Aims: Phytosterolemia is a rare genetic disease caused by mutation of the ABCG5/8 gene. Our aim was to elucidate the natural history and homeostasis of phytosterolemia.

Methods: We analyzed a Hutterite kindred consisting of 21 homozygotes with phytosterolemia assembled over a period of two decades, all of whom carried the ABCG8 S107X mutation and were treated with ezetimibe.

Thyroid Hormone Status in Sitosterolemia Is Modified by Ezetimibe.

Objectives: To assess the association between biomarkers of thyroid status and 5α-stanols in patients with sitosterolemia treated with ezetimibe (EZE).

Study Design: Eight patients with sitosterolemia (16-56 years of age) were studied during 14 weeks off EZE therapy and 14 weeks on EZE (10 mg/day). Serum thyroid biomarkers (free triiodothyronine [FT3], free thyroxine [FT4], FT3/FT4 ratio, thyroid-stimulating hormone), 5α-stanols (sitostanol and cholestanol), and cholestanol precursors (total cholesterol and its synthesis marker lathosterol, and 7α-hydroxy-4-cholesten-3-one cholestenol) were measured at baseline and during the 14 weeks off EZE and on EZE.

Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia.

Background And Aims: Sitosterolemia displays high plasma total sterols [high plant sterols (PS) + normal to high total cholesterol (TC)] with normal to moderately elevated low-density lipoprotein (LDL) levels. High LDL, intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, low high-density lipoprotein (HDL), and increased non-HDL and the ratios of TC and triglycerides (TG) to HDL can increase the risk for atherosclerosis. Ezetimibe (EZE) can reduce plasma PS and TC levels in sitosterolemia, but its effect on lipoprotein subclasses has not been previously reported.

Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia.

Objective: To assess if ezetimibe (EZE), a sterol-absorption inhibitor, improves platelet (PLT) count and size relative to its effect on plasma plant sterol (PS) in patients with sitosterolemia (STSL).

Study Design: Patients with STSL (5 males, 3 females, 16-56 years of age) receiving EZE intervention as part of their routine care participated in this study. EZE was discontinued for 14 weeks (off) and then resumed for another 14 weeks (on).

Serum lipids, plant sterols, and cholesterol kinetic responses to plant sterol supplementation in phytosterolemia heterozygotes and control individuals.

Background: Plant sterol (PS) supplementation is increasingly accepted as a dietary strategy to lower plasma cholesterol concentrations. However, information is scarce about the effect of increased PS intake in potentially vulnerable groups, such as phytosterolemia heterozygotes (HET).

Objective: This study assessed the responsiveness of circulating PS and lipid concentrations and cholesterol kinetics (absorption and synthesis) to daily PS supplementation in HET (ABCG8 S107X mutation) compared with a healthy control cohort.

Mifepristone treatment results in differential regulation of glycerolipid biosynthesis in baby hamster kidney cells expressing a mifepristone-inducible ABCA1.

ATP binding cassette A1 (ABCA1) transports cholesterol, phospholipids and lipophilic molecules to and across cellular membranes. We examined if ABCA1 expression altered cellular de novo glycerolipid biosynthesis in growing Baby hamster kidney (BHK) cells. Mock BHK cells or cells expressing a mifepristone-inducible ABCA1 (ABCA1) were incubated plus or minus mifepristone and then with [(3)H]serine or [(3)H]inositol or [(3)H]ethanolamine or [methyl-(3)H]choline or [(3)H]glycerol or [(14)C]oleate and radioactivity incorporated into glycerolipids determined.

Iatrogenic severe depression of high-density lipoprotein cholesterol.

The authors present 5 cases of paradoxical depression of high-density lipoprotein (HDL) cholesterol induced by fibrate drugs. In a 24-month review of all cases seen in one physician's practice at the Winnipeg Health Sciences Centre Lipid Clinic, 492 patients made a total of 1187 visits. Sixty-eight of them were given a fibrate drug (14%).

Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Elevated plasma homocysteine (Hcy) concentration is associated with other cardiovascular risk factors. We previously reported that Hcy stimulated cholesterol biosynthesis in HepG2 cells.

Phenotypic heterogeneity of sitosterolemia.

Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3.

Lipids and atherosclerosis.

Atherosclerosis is the leading cause of death in North America and within the next two decades will be the leading cause worldwide. Atherosclerosis is characterized by vascular obstruction from the deposits of plaque, resulting in reduced blood flow. Plaque rupture and the consequent thrombosis may lead to sudden blockage of the arteries and cause heart attack.

Cyclooxygenase expression is elevated in retinoic acid-differentiated U937 cells.

Cyclooxygenase (COX) is the rate-limiting enzyme for the biosynthesis of prostaglandins in monocytes/macrophages. The COX-1 is constitutively expressed in most tissues and may be involved in cellular homeostasis, whereas the COX-2 is an inducible enzyme that may play an important role in inflammation and mitogenesis. When U937 monocytic cells were incubated with retinoic acid (RA) for 48 h, cell differentiation took place with concomitant increases in prostaglandin E2 (PGE2) production and COX activity.

Modulation of cytosolic phospholipase A(2) by PPAR activators in human preadipocytes.

Cytosolic phospholipase A(2) (cPLA(2)) is responsible for the release of arachidonic acid, a precursor for eicosanoid biosynthesis, from cellular phospholipids. The objective of this study is to examine the regulation of cPLA(2) by peroxisome proliferator-activated receptor (PPAR) activators in preadipocyte SW872 (SW) cells. PPAR belong to the superfamily of nuclear hormone receptors that heterodimerize with the retinoid X receptor.

Fatty infiltration of liver in hyperlipidemic patients.

Hyperlipidemia is a known risk factor for fatty infiltration of the liver, a condition that can progress to cirrhosis and liver failure. The objectives of this study were to document the prevalence of fatty infiltration in the livers of hyperlipidemic patients and to identify the predictor variables associated with this condition. Over an 18-month recruitment period, clinical, biochemical, and radiologic assessments were performed in a cross-sectional manner in 95 adult patients referred to an urban hospital-based lipid clinic for evaluation and management of hyperlipidemia.

Evaluation of a new apolipoprotein(a) isoform-independent assay for serum Lipoprotein(a).

The risk factor, Lipoprotein(a), [(Lp(a)], has been measured in numerous clinical studies by a variety of immunochemical assay methods. It is becoming apparent that for many of these assays antibody specificity towards the apolipoprotein(a) [apo(a)] repetitive component [the kringle 4-type 2 repeats] and apo(a) size heterogeneity can significantly affect the accuracy of serum Lp(a) measurements. To address this issue, we investigated whether our current in house Lp(a) [Mercodia] assay showed such bias compared to a recently available assay [Apo-Tek], claiming to possess superior capability for isoform-independent measurement of Lp(a).

Atherosclerosis risk factors: the possible role of homocysteine.

Atherosclerosis is the leading cause of death in North America. It is characterized by thickening of the coronary artery wall by the formation of plaques, resulting in reduced blood flow. Plaque rupture and the consequent thrombosis may lead to sudden blockage of arteries and causing stroke and heart attack.

The effect of fenofibrate treatment on endothelium-dependent relaxation induced by oxidative modified low density lipoprotein from hyperlipidemic patients.

The objective of the research project was to investigate whether fenofibrate treatment may alter the biochemical content of the oxidized LDL and consequently its ability to impair the endothelium-dependent relaxation in hyperlipidemic patients. We hypothesized that fenofibrate treatment of hyperlipidemic patients may attenuate the ability of their oxidized LDL to impair the endothelium-dependent relaxation of the blood vessels as a consequence of fenofibrate-induced changes to the content and composition of lysoPC in the LDL molecule. Hyperlipidemic patients (Type IIb and Type IV) were recruited from the Lipid Clinic, HSC, Winnipeg, Canada, for this study.

Effects of atorvastatin treatment on the oxidatively modified low density lipoprotein in hyperlipidemic patients.

Atorvastatin is an established HMG-CoA reductase inhibitor which effectively reduces the plasma low density lipoprotein (LDL)-cholesterol level in hyperlipidemic patients. The present study was designed to investigate whether atorvastatin treatment can modify the biochemical content of oxidized LDL in hyperlipidemic patients and the ability of oxidized LDL to impair the endothelium-dependent relaxation of blood vessels. With atorvastatin (10 mg/day) treatment for 4 weeks in 19 type IIa hyperlipidemic patients, total cholesterol level was lowered by 23%, LDL-cholesterol was lowered by 32% and triacylglycerol was lowered by 19% as compared with dietary therapy alone.

Oxidative modification of low density lipoprotein in normal and hyperlipidemic patients: effect of lysophosphatidylcholine composition on vascular relaxation.

The elevated level of plasma low density lipoprotein (LDL) in hyperlipidemic patients is an important risk factor for the production of atherosclerosis. Plasma LDL must be modified before it can produce an impairment of endothelium-dependent relaxation in aortic rings or enhancement of uptake by macrophages. The dramatic increase in lysophosphatidylcholine (lysoPC) content in oxidatively modified LDL has been touted as an important biochemical factor for the impairment of endothelium-dependent relaxation.

Polymorphism and peripheral levels of apolipoprotein(a) in polygenic hypercholesterolemia and combined hyperlipidemia.

This study demonstrates that peripheral apolipoprotein(a) [apo(a)] levels are higher in patients with polygenic hypercholesterolemia (PH) and combined hyperlipidemia (CH) than in controls. Levels of apo(a) inversely correlate with apo(a) isoform sizes. For a given apo(a) isoform, apo(a) levels are higher in PH and CH patients.

Alteration of lysophosphatidylcholine content in low density lipoprotein after oxidative modification: relationship to endothelium dependent relaxation.

Objective: The aim was to examine the formation of lipid peroxidation products and the alteration in phospholipid content in low density lipoprotein (LDL) after oxidative modification by CuSO4, and subsequently, to determine the ability of the modified LDL to impair endothelium dependent relaxation in rat aortic rings.

Methods: Blood samples were obtained from normal human volunteers. LDL was prepared by sequential ultracentrifugation and it was oxidatively modified in the presence of 5 microM CuSO4.

Serum lipid profile determines platelet reactivity to native and modified LDL-cholesterol in humans.

The effects of thrombin (0.2 U/ml) and native (n-LDL), malondialdehyde-modified (MDA-LDL) and auto-oxidized (ox-LDL) low-density lipoproteins (20 micrograms of protein/ml) on platelet activation were evaluated in seven hyperlipidemic patients and compared to seven controls (fasting serum cholesterol 8.49 +/- 0.