The changes of the composition of blood lipoproteins caused by menopause could also change the effect of hypolipidemic therapy. Using an experimental model we studied the changes of serum lipids and the effect of immediate or delayed treatment with simvastatin on atherosclerosis after surgical menopause. Female golden Syrian hamster aged 6 months were fed hypercholesterolemic diet during the whole study. Atherosclerotic changes in thoracic and abdominal aortas were assessed by stereomicroscopic method after 12 weeks. Four experimental groups were studied: sham-operated animals (n=5), ovariectomized animals (n=9), ovariectomized animals treated for 12 weeks (n=10), and ovariectomized animals treated 4 weeks after ovariectomy for 8 weeks (n=9). The dose of simvastatin was 10 mg/kg of body weight. After 12 weeks, ovariectomized animals had tenfold higher concentration of triglycerides in LDL fraction and significantly higher prevalence of atherosclerosis than animals without ovariectomy. Treatment with simvastatin substantially decreased the prevalence of atherosclerotic changes, but otherwise did not change individual serum lipids including LDL cholesterol. However, it improved proportions of pro- and antiatherogenic serum lipids mainly by the increase of HDL cholesterol. The timing of simvastatin treatment had no significant effect on atherosclerotic changes or lipid parameters. Simvastatin treatment partly prevented atherosclerotic changes induced by ovariectomy. This effect was not mediated by decrease of LDL cholesterol, but by increase in HDL cholesterol.
- MeSH
- aorta abdominalis patologie účinky léků MeSH
- aorta thoracica patologie účinky léků MeSH
- ateroskleróza krev patologie prevence a kontrola MeSH
- biologické markery krev MeSH
- časové faktory MeSH
- financování organizované MeSH
- HDL-cholesterol krev MeSH
- křečci praví MeSH
- křeček rodu Mesocricetus MeSH
- LDL-cholesterol krev MeSH
- lipoproteiny LDL krev MeSH
- modely nemocí na zvířatech MeSH
- nemoci aorty krev patologie prevence a kontrola MeSH
- ovarektomie MeSH
- rozvrh dávkování léků MeSH
- simvastatin aplikace a dávkování farmakologie MeSH
- statiny aplikace a dávkování farmakologie MeSH
- triglyceridy krev MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
PHHC rats represent a suitable experimental model of polygenic hypercholesterolemia. It has been found that its metabolic defect is not related to alimentary cholesterol absorption and LDL clearance. We have tested possible changes in cholesterol clearance from the liver to bile acids by analysis of the expression of the cholesterol 7alpha-hydroxylase (cyp7A1) gene in PHHC (N = 20) and Wistar (controls) (N = 19) male rats. The animals were fed standard laboratory diet (CD) or control diet containing 5% fat and 2% cholesterol (HCD) for two weeks. SSCP and RT-PCR were used for mutation analysis and study of gene expression, respectively. Although the basal cholesterolemia in PHHC was similar to controls (1.80 +/- 0.48 and 1.52 +/- 0.39 mmol/l, respectively), it rose in rats fed on HCD to 9.81 +/- 1.65 mmol/l in PHHC rats and only to 2.19 +/- 0.41 mmol/l in controls. Similarly to the basal cholesterol concentration, the gene expression of cyp7A1 in the liver of rats on CD was the same in both compared groups on the control diet. In controls on HCD, cyp7A1 gene expression increased almost 4-fold immediately on the first day and achieved up to approximately 20-multiple basal expression in the end of the feeding period. Compared to the controls, after switching to HCD the cyp7A1 gene expression in PHHC rats did not change dramatically. These results suggest that the cyp7A1 gene plays an important role in development of hypercholesterolemia in PHHC rats.
- MeSH
- cholesterol-7-alfa-hydroxylasa genetika metabolismus MeSH
- cholesterol krev MeSH
- dieta MeSH
- krysa rodu rattus MeSH
- lipoproteiny krev MeSH
- mutantní kmeny potkanů MeSH
- nukleové kyseliny metabolismus MeSH
- potkani Wistar MeSH
- regulace genové exprese enzymů MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
BACKGROUND: The relationship between dietary composition and plasma lipids is to some extent genetically determined. It has been found that variants of some genes (e.g., apolipoprotein E and cholesterol 7-alpha hydroxylase) play an important role in changes in plasma lipid levels in response to dietary intervention. We analyzed the effect of variation in the apolipoprotein (APO) APOA1/C3/A4/A5 gene cluster on decreases in plasma cholesterol levels over an 8-year follow-up study. METHODS: Men (n=133) from the Czech population, for which dietary composition has markedly changed (red meat 80-->68 kg/person/year, animal fat 16-->9 kg/person/year, fruits and vegetables 133-->150 kg/person/year) were recruited. APOA1 (G-75>A and C83>T), APOC3 (C-482>T and C3238>G), APOA4 (Thr347>Ser and Gln360His) and APOA5 (T-1131>C, Ser19>Trp and Val153>Met) variants were analyzed by PCR and restriction analysis. Lipid levels were analyzed in 1988 and 1996. Dietary information was obtained from the Institute of Agricultural Economy. RESULTS: In APOA5 Ser19Ser homozygotes (n=105), plasma cholesterol was relatively stable over the years (6.1+/-1.3 and 5.6+/-1.0 mmol/L in 1988 and 1996), but the decrease was much higher in Trp19 carriers (n=27; 6.5+/-1.6 vs. 5.1+/-1.1 mmol/L). This difference in change is significant at p<0.005. Similarly, a better response to dietary changes was detected in carriers of the common APOA4 haplotypes Thr-347Thr/Gln360Gln and Thr347Ser/Gln360Gln (n=102; 6.3+/-1.3 and 5.5+/-1.1 mmol/L in 1988 and 1996, p<0.001). Total cholesterol was relatively stable over time in carriers (n=18) of at least one His360 allele and/or two Ser347 alleles (5.7+/-1.1 and 5.5+/-0.9 mmol/L in 1988 and 1996, n.s.). Other variants analyzed did not influence the change in lipid measurements over time. CONCLUSIONS: APOA4 and APOA5 variants may play an important role in the individual sensitivity of lipid parameters to dietary composition in men.
- MeSH
- apolipoprotein A-I genetika MeSH
- apolipoproteiny A genetika MeSH
- cholesterol krev MeSH
- dieta MeSH
- DNA genetika izolace a purifikace MeSH
- dospělí MeSH
- financování organizované MeSH
- genetická variace MeSH
- homozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- multigenová rodina MeSH
- následné studie MeSH
- polymorfismus genetický MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
The relationship between dietary composition/cholesterol-lowering therapy and final plasma lipid levels is to some extent genetically determined. It is clear that these responses are under polygenic control, with multiple variants in many genes participating in the total effect (and with each gene contributing a relatively small effect). Using different experimental approaches, several candidate genes have been analyzed to date.Interesting and consistent results have been published recently regarding the A-204C promoter variant in the cholesterol 7alpha-hydroxylase (CYP7A1) gene. CYP7A1 is a rate-limiting enzyme in bile acid synthesis and therefore plays an important role in maintaining cholesterol homeostasis. CYP7A1-204CC homozygotes have the greatest decrease in total cholesterol level in response to dietary changes in different types of dietary intervention studies. In contrast, one study has reported that the effect of statins in lowering low-density lipoprotein (LDL)-cholesterol levels was slightly greater in -204AA homozygotes.The CYP7A1 A-204C variant accounts for a significant proportion of the genetic predisposition of the response of plasma cholesterol levels.
- MeSH
- anticholesteremika terapeutické užití MeSH
- cholesterol-7-alfa-hydroxylasa genetika MeSH
- dieta MeSH
- farmakogenetika MeSH
- financování organizované MeSH
- kardiovaskulární nemoci farmakoterapie genetika MeSH
- LDL-cholesterol krev metabolismus MeSH
- lidé MeSH
- přijímání potravy genetika MeSH
- statiny terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
