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1.
Lipids ; 55(2): 193-198, 2020 03.
Article in English | MEDLINE | ID: mdl-32065674

ABSTRACT

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 [14 C]acetate for 24 h and the radioactivity incorporated into lipids determined. Cells incubated with CSC exhibited a 40% reduction in cholesterol esterification (p < 0.05) compared to cells incubated with cholesterol alone. In addition, a 17.5-fold reduction (p < 0.05) in total cholesterol (cholesterol plus cholesteryl ester) synthesis from [14 C]acetate was observed in cells incubated with CSC compared to cholesterol alone. Low-density lipoprotein receptor (LDLR) mRNA abundance was lower in cells incubated with CSC compared to cells incubated with cholesterol alone. Our results suggest that incubation of HepG2 cells with a ratio of sterols that mimic the plasma concentration seen in phytosterolemia patients reduces cholesterol esterification, total cholesterol synthesis, and inhibits LDLR mRNA abundance. We suggest that future cell and animal-based work on phytostosterolemia might employ this methodology to serve as a novel paradigm of the disease.


Subject(s)
Cholesterol/analogs & derivatives , Cholesterol/pharmacology , Hypercholesterolemia/genetics , Intestinal Diseases/genetics , Lipid Metabolism, Inborn Errors/genetics , Phytosterols/adverse effects , Receptors, LDL/genetics , Sitosterols/pharmacology , Carbon Radioisotopes/pharmacology , Cholesterol Esters/metabolism , Down-Regulation , Gene Expression Profiling , Gene Expression Regulation/drug effects , Hep G2 Cells , Humans , Hypercholesterolemia/metabolism , Intestinal Diseases/metabolism , Lipid Metabolism, Inborn Errors/metabolism , Models, Biological , Phytosterols/genetics , Phytosterols/metabolism , Phytosterols/pharmacology
2.
Nutr Rev ; 76(10): 725-746, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30101294

ABSTRACT

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. Variations in interindividual responses to plant sterols and stanols, as well as the personalization of lipid-lowering therapies, were addressed. Finally, the clinical aspects and treatment of sitosterolemia were reviewed. Although plant sterols and stanols continue to offer an efficacious and convenient dietary approach to cholesterol management, long-term clinical trials investigating the endpoints of cardiovascular disease are still lacking.


Subject(s)
Anticholesteremic Agents/pharmacology , Cardiovascular Diseases/therapy , Diet/methods , Hypercholesterolemia/therapy , Intestinal Diseases/therapy , Lipid Metabolism, Inborn Errors/therapy , Phytosterols/adverse effects , Phytosterols/pharmacology , Canada , Cardiovascular Diseases/blood , Cholesterol/blood , Cholesterol, LDL/blood , Congresses as Topic , Humans , Hypercholesterolemia/blood , Intestinal Diseases/blood , Lipid Metabolism, Inborn Errors/blood , Phytosterols/blood
3.
Atherosclerosis ; 269: 122-128, 2018 02.
Article in English | MEDLINE | ID: mdl-29353227

ABSTRACT

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. RESULTS: Most of these subjects were asymptomatic and devoid of clinical stigmata, and this, since they were ascertained primarily by a process of cascade testing, suggests that, relative to its true prevalence, phytosterolemia is a condition of low morbidity. All subjects have responded well to treatment with ezetimibe. Initial (pre-treatment) and post-ezetimibe levels of cholesterol and sitosterol were measured and percentage changes on ezetimibe were calculated. We found initial levels to be inversely related to subjects' ages as were percentage responses to ezetimibe therapy. There was also a direct correlation between initial levels and percentage responses to ezetimibe. Hence on-treatment levels were very uniform. CONCLUSIONS: This evidence of a link with age leads us to propose that an age-related change in cholesterol and sterol homeostasis occurs at puberty in phytosterolemia and that the change is due to high sterol and/or stanol levels causing feedback inhibition of sterol regulatory element-binding protein (SREBP-2) processing. This would explain the well-documented phenomenon of depressed cholesterol synthesis in phytosterolemia. It is also well-known that LDL-receptor activity is increased, and this feasibly explains reduced LDL levels and consequent reduction of plasma cholesterol and sitosterol levels. Downregulated SREBP-2 processing would be expected to also lower proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and this would explain high LDL-receptor activity. The above state could be termed disrupted homeostasis and the alternative, seen mostly in children and characterized by hypercholesterolemia and hypersterolemia, simple homeostasis.


Subject(s)
Anticholesteremic Agents/therapeutic use , Ezetimibe/therapeutic use , Hypercholesterolemia/drug therapy , Hypercholesterolemia/epidemiology , Intestinal Diseases/drug therapy , Intestinal Diseases/epidemiology , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/epidemiology , Phytosterols/adverse effects , Phytosterols/blood , Rare Diseases/drug therapy , Rare Diseases/epidemiology , ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , Adolescent , Adult , Age Factors , Asymptomatic Diseases , Biomarkers/blood , Canada/epidemiology , Child , Child, Preschool , Cholesterol/blood , Female , Genetic Predisposition to Disease , Homeostasis , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/genetics , Infant , Intestinal Diseases/blood , Intestinal Diseases/genetics , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/genetics , Male , Middle Aged , Mutation , Phenotype , Phytosterols/genetics , Prevalence , Puberty , Rare Diseases/blood , Rare Diseases/genetics , Risk Factors , Sitosterols/blood , Time Factors , Treatment Outcome , United States/epidemiology , Young Adult
4.
J Pediatr ; 188: 198-204.e1, 2017 09.
Article in English | MEDLINE | ID: mdl-28625503

ABSTRACT

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. RESULTS: EZE increased FT3/FT4 (10% ± 4%; P = .02). EZE reduced plasma and red blood cells sitostanol (-38% ± 6% and -20% ± 4%; all P < .05) and cholestanol (-18% ± 6% and -13% ± 3%; all P < .05). The change in plasma cholestanol level on EZE inversely correlated with the change in FT3/FT4 (r = -0.86; P = .01). EZE lowered total cholesterol (P < .0001) and did not affect 7α-hydroxy-4-cholesten-3-one cholestanol. EZE increased (P < .0001) lathosterol initially, but the level was not sustained, resulting in similar levels at week 14 off EZE and on EZE. CONCLUSION: In patients with STSL, 5α-stanols levels might be associated with thyroid function. EZE reduces circulating 5α-stanols while increasing FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. TRIAL REGISTRATION: ClinicalTrials.govNCT01584206.


Subject(s)
Anticholesteremic Agents/therapeutic use , Ezetimibe/therapeutic use , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Intestinal Diseases/blood , Intestinal Diseases/drug therapy , Lipid Metabolism, Inborn Errors/blood , Lipid Metabolism, Inborn Errors/drug therapy , Phytosterols/adverse effects , Adolescent , Adult , Cholestanol/blood , Cholestenones/blood , Cholesterol/blood , Female , Humans , Male , Middle Aged , Phytosterols/blood , Sitosterols/blood , Thyrotropin/blood , Thyroxine/blood , Triiodothyronine/blood , Young Adult
5.
Atherosclerosis ; 260: 27-33, 2017 05.
Article in English | MEDLINE | ID: mdl-28340366

ABSTRACT

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. METHODS: Sitosterolemia patients (n = 8) were taken off EZE for 14 weeks (OFF EZE) and placed on EZE (10 mg/d) for 14 weeks (ON EZE). Serum lipids were measured enzymatically and lipoprotein subclasses were assessed by polyacrylamide gel electrophoresis. RESULTS: EZE reduced (p < 0.05) total sterols (-12.5 ± 4.1%) and LDL-sterol (-22.7 ± 5.7%) and its sterol mass of large VLDL (-24.4 ± 4.5%), VLDL remnants (-21.1 ± 7.9%) and large IDL (-22.4 ± 7.2%) compared to OFF EZE. EZE did not affect large LDL subclasses or mean LDL particle size (273.8 ± 0.6 vs. 274.6 ± 0.3 Å). EZE increased HDL-sterol (25.5 ± 8.0%, p = 0.008) including intermediate (34 ± 14%, p = 0.02) and large (33 ± 16%, p = 0.06) HDL. EZE reduced non-HDL-sterol (-21.8± 5.0%), total sterols/HDL (-28.2 ± 5.5%) and TG/HDL (-27.4 ± 6.5%, all p < 0.01). CONCLUSIONS: EZE improves VLDL and HDL subfraction distribution, thereby reducing the atherogenic lipid profile, thus providing potential clinical benefit in sitosterolemia beyond TC and PS reduction.


Subject(s)
Ezetimibe/therapeutic use , Hypercholesterolemia/drug therapy , Intestinal Diseases/drug therapy , Lipid Metabolism, Inborn Errors/drug therapy , Lipoproteins, HDL/blood , Lipoproteins, VLDL/blood , Phytosterols/adverse effects , Adolescent , Adult , Anticholesteremic Agents/therapeutic use , Cholesterol, HDL/blood , Electrophoresis, Polyacrylamide Gel , Female , Humans , Hypercholesterolemia/blood , Intestinal Diseases/blood , Lipid Metabolism, Inborn Errors/blood , Lipoproteins, HDL/drug effects , Lipoproteins, IDL/blood , Lipoproteins, IDL/drug effects , Lipoproteins, VLDL/drug effects , Male , Middle Aged , Phytosterols/blood , Treatment Outcome , Young Adult
6.
J Pediatr ; 166(1): 125-31, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25444527

ABSTRACT

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). Hematology variables along with plasma and red blood cells (RBC) PS and total cholesterol (TC) levels were measured at the end of each phase. RESULTS: EZE increased PLT count (23% ± 9%) and decreased mean PLT volume (MPV; 10% ± 3%, all P < .05). In patients off EZE, PLT counts inversely correlated (r = -0.96 and r = -0.91, all P < .01) with plasma and RBC PS to TC ratio (PS/TC), and MPV positively correlated (r = 0.91, P = .03 and r = 0.93, P = .02) with plasma and RBC PS/TC. EZE reduced plasma and RBC sitosterol (-35% ± 4% and -28% ± 3%), total PS (-37% ± 4% and -28% ± 3%, all P < .0001) levels, and PS/TC (-27% ± 4% and -28% ± 4%, P < .01). CONCLUSIONS: EZE reduces plasma and RBC PS levels, while increasing PLT count and decreasing MPV, and thereby may reduce the risk for bleeding in STSL. Plasma PS levels and ABCG5/ABCG8 genes should be analyzed in patients with unexplained hematologic abnormalities.


Subject(s)
Anticholesteremic Agents/therapeutic use , Azetidines/therapeutic use , Cholesterol/blood , Hypercholesterolemia/drug therapy , Intestinal Diseases/drug therapy , Lipid Metabolism, Inborn Errors/drug therapy , Phytosterols/adverse effects , Phytosterols/blood , Platelet Count , Adolescent , Adult , Anticholesteremic Agents/administration & dosage , Azetidines/administration & dosage , Canada , Erythrocyte Count , Ezetimibe , Female , Humans , Hypercholesterolemia/blood , Intestinal Diseases/blood , Lipid Metabolism, Inborn Errors/blood , Male , Middle Aged , Pilot Projects , Treatment Outcome , United States , Young Adult
7.
Am J Clin Nutr ; 95(4): 837-44, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22378727

ABSTRACT

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. DESIGN: A double-blind, randomized, crossover, placebo-controlled study was conducted in 10 HET and 15 control subjects. The participants had a mean (±SEM) age of 34 ± 2 y and a BMI (in kg/m²) of 29.9 ± 1.1 and consumed ∼1.6 g PS or placebo capsules daily with supper for 4 wk. Cholesterol absorption and synthesis were assessed by using [¹³C]cholesterol and deuterium oxide, respectively. RESULTS: Plasma LDL-cholesterol concentrations decreased (P = 0.006) in both groups after PS supplementation (HET: 2.73 ± 0.19 mmol/L; control: 3.11 ± 0.19 mmol/L) compared with placebo (HET: 3.12 ± 0.20 mmol/L; control: 3.50 ± 0.21 mmol/L), whereas PS concentrations (campesterol+ß-sitosterol) increased (P = 0.03) in both groups after PS supplementation (HET: 39.72 ± 6.05 µmol/L; control: 24.03 ± 1.65 µmol/L) compared with placebo (HET: 27.32 ± 3.80 µmol/L; control: 21.12 ± 2.05 µmol/L). Cholesterol absorption efficiency decreased (P = 0.010) by ∼22% and ∼17% and synthesis rates increased (P = 0.040) by ∼20% and ∼24% in the HET and control groups, respectively, in response to PS consumption compared with placebo. CONCLUSION: These data suggest that heterozygosity for the ABCG8 S107X mutation does not influence the action of dietary PS on circulating cholesterol concentrations but may affect sterol absorption.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Cholesterol/metabolism , Dietary Supplements , Hypercholesterolemia/diet therapy , Intestinal Diseases/diet therapy , Lipid Metabolism, Inborn Errors/diet therapy , Lipids/blood , Phytosterols/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 8 , ATP-Binding Cassette Transporters/chemistry , Adolescent , Adult , Aged , Amino Acid Substitution , Cholesterol/biosynthesis , Cholesterol/blood , Cohort Studies , Cross-Over Studies , Double-Blind Method , Female , Heterozygote , Humans , Hypercholesterolemia/etiology , Hypercholesterolemia/genetics , Hypercholesterolemia/metabolism , Hypercholesterolemia/physiopathology , Hypercholesterolemia/prevention & control , Intestinal Absorption , Intestinal Diseases/genetics , Intestinal Diseases/metabolism , Intestinal Diseases/physiopathology , Kinetics , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/metabolism , Lipid Metabolism, Inborn Errors/physiopathology , Male , Middle Aged , Mutant Proteins/chemistry , Mutant Proteins/genetics , Phytosterols/adverse effects , Phytosterols/blood , Phytosterols/genetics , Phytosterols/metabolism , Young Adult
8.
Lipids ; 46(9): 795-804, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21710238

ABSTRACT

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. Mifepristone did not affect [1,3-(3)H]glycerol or [(14)C]oleate or [(3)H]ethanolamine or [methyl-(3)H]choline uptake in BHK cells. In contrast, [(3)H]glycerol and [(14)C]oleate incorporated into phosphatidylserine (PtdSer) were elevated 2.4-fold (p < 0.05) and 54% (p < 0.05), respectively, upon ABCA1 induction confirming increased PtdSer biosynthesis from these precursors. However, mifepristone inhibited [(3)H]serine uptake and incorporation into PtdSer indicating that PtdSer synthesis from serine in BHK cells is dependent on serine uptake. Mifepristone stimulated [(3)H]inositol uptake in mock and ABCA1 cells but not its incorporation into phosphatidylinositol indicating that its synthesis from inositol is independent of inositol uptake in BHK cells. [(3)H]glycerol and [(14)C]oleate incorporated into triacylglycerol were reduced and into diacylglycerol elevated only in mifepristone-induced ABCA1 expressing cells due to a decrease in diacylglycerol acyltransferase-1 (DGAT-1) activity. The presence of trichostatin A, a class I and II histone deacetylase inhibitor, reversed the ABCA1-mediated reduction in DGAT-1 activity but did not affect DGAT-1 mRNA expression. Thus, mifepristone has diverse effects on de novo glycerolipid synthesis. We suggest that caution should be exercised when using mifepristone-inducible systems for studies of glycerolipid metabolism in cells expressing glucocorticoid responsive receptors.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Gene Expression/drug effects , Glycerides/biosynthesis , Mifepristone/pharmacology , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Cell Line , Cricetinae , Diacylglycerol O-Acyltransferase/genetics , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Assays , Glycerol/metabolism , Glycerophospholipids/metabolism , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Inositol/metabolism , Oleic Acid/metabolism , Phosphatidylserines/biosynthesis , Serine/metabolism
9.
Am J Physiol Endocrinol Metab ; 288(5): E1002-10, 2005 May.
Article in English | MEDLINE | ID: mdl-15644462

ABSTRACT

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. In the present study, we investigated the underlying mechanisms of Hcy-induced hepatic cholesterol biosynthesis in an animal model. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase were significantly increased in livers of hyperhomocysteinemic rats. There were marked hepatic lipid accumulation and an elevation of plasma cholesterol concentration in hyperhomocysteinemic rats. Three transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element-binding protein (CREB), and nuclear factor Y (NF-Y) were activated in livers of hyperhomocysteinemic rats. Upon Hcy treatment of hepatocytes, there was a significant increase in HMG-CoA reductase mRNA expression in these cells. The activation of SREBP-2, CREB, and NF-Y preceded the increase in HMG-CoA reductase expression in Hcy-treated cells. Pretreatment of hepatocytes with inhibitors for transcription factors not only blocked the activation of SREBP-2, CREB, and NF-Y but also attenuated Hcy-induced HMG-CoA reductase mRNA expression. These results suggested that hyperhomocysteinemia-induced activation of SREBP-2, CREB, and NF-Y was responsible for increased cholesterol biosynthesis by transcriptionally regulating HMG-CoA reductase expression in the liver leading to hepatic lipid accumulation and subsequently hypercholesterolemia. In conclusion, the stimulatory effect of Hcy on hepatic cholesterol biosynthesis may represent an important mechanism for hepatic lipid accumulation and cardiovascular disorder associated with hyperhomocysteinemia.


Subject(s)
Acyl Coenzyme A/metabolism , Cholesterol/biosynthesis , Homocysteine/blood , Hyperhomocysteinemia/metabolism , Lipid Metabolism , Liver/metabolism , Transcription Factors/metabolism , Animals , Male , Rats , Rats, Sprague-Dawley , Signal Transduction/physiology
10.
J Lipid Res ; 45(12): 2361-7, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15375183

ABSTRACT

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. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or ABCG8.


Subject(s)
Sitosterols/blood , Xanthomatosis/physiopathology , ATP Binding Cassette Transporter, Subfamily G, Member 5 , ATP Binding Cassette Transporter, Subfamily G, Member 8 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , Female , Humans , Lipoproteins/genetics , Lipoproteins/metabolism , Male , Middle Aged , Molecular Sequence Data , Pedigree , Phenotype
11.
Biochem Cell Biol ; 82(1): 212-24, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15052339

ABSTRACT

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. High serum lipid levels, especially the elevated level of low-density lipoprotein (LDL), have been shown to be strongly related to the development of atherosclerosis. It is generally accepted that atherosclerotic lesions are initiated via an enhancement of LDL uptake by monocytes and macrophages. In the liver, uptake of plasma LDL is mediated via specific LDL receptors, but a scavenger receptor system is employed by macrophages. Plasma LDL must be modified prior to uptake by macrophages. Analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated, and the high level of the lysolipid was shown to impair the endothelium-dependent relaxation of the blood vessels. In a separate study, we showed that a high level of homocysteine caused the increase in cholesterol production and apolipoprotein B-100 secretion in hepatic cells. Statins have been used effectively to control the production of cholesterol in the liver, and recently, ezetimibe has been shown to supplement the efficacy of statins by inhibiting cholesterol absorption. The factor of elevated levels of triglyceride-rich lipoproteins in association with depressed high-density lipoproteins, usually in the context of insulin resistance, is an important contributor to atherosclerosis and can be effectively treated with fibric acid derivatives. In hyperhomocysteinemia, folic acid supplements may have a role in the control of cholesterol by reducing the plasma homocysteine level.


Subject(s)
Arteriosclerosis/genetics , Arteriosclerosis/metabolism , Lipids/blood , Arteriosclerosis/etiology , Chemokines/genetics , Chemokines/metabolism , Cholesterol/metabolism , Endothelium, Vascular/metabolism , Homocysteine/blood , Homocysteine/metabolism , Humans , Hyperhomocysteinemia/etiology , Hyperhomocysteinemia/genetics , Hyperhomocysteinemia/metabolism , Hyperlipidemias/genetics , Hyperlipidemias/metabolism , Hyperlipidemias/therapy , Lipoproteins, LDL/metabolism , Lipoproteins, LDL/physiology , Risk Factors
12.
Biochim Biophys Acta ; 1633(1): 51-60, 2003 Jul 04.
Article in English | MEDLINE | ID: mdl-12842195

ABSTRACT

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. In this study, the mechanism of RA (all-trans- or 9-cis-RA)-induced enhancement of PGE2 biosynthesis in U937 cells was examined. Treatment of cells with all-trans- or 9-cis-RA up to 48 h caused an increase in PGE2 production in a time- and dose-dependent manner. Both RA isomers caused the enhancement of PGE2 production and the up-regulation of COX-1 expression at the protein and mRNA levels. The increase in COX-1 mRNA was found to precede the increase in COX-1 protein expression. Interestingly, the COX-2 protein and COX-2 mRNA were not detected in U937 cells, and their levels remained undetectable during the entire course of RA treatment. We conclude that treatment of U937 cells by RA for 48 h caused the initiation of cell differentiation, which was found to be concomitant with a significant increase in PGE2 production mediated via the up-regulation of COX-1 mRNA and protein expression.


Subject(s)
Cell Differentiation/drug effects , Gene Expression Regulation, Enzymologic , Isoenzymes/drug effects , Monocytes/enzymology , Prostaglandin-Endoperoxide Synthases/metabolism , Tretinoin/pharmacology , Antineoplastic Agents/pharmacology , Dinoprostone/biosynthesis , Dose-Response Relationship, Drug , Humans , Isoenzymes/genetics , Isoenzymes/metabolism , Isomerism , Kinetics , Monocytes/drug effects , Monocytes/metabolism , Prostaglandin-Endoperoxide Synthases/genetics , RNA, Messenger/analysis , Tretinoin/chemistry , Tumor Cells, Cultured , U937 Cells
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