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| Author(s): |
Simone Sorkin Arazi
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2008-12-09 |
| Examining board members: |
Rosario Dominguez Crespo Hirata;
Egidio Lima Dorea;
Silvya Stuchi Maria Engler;
Edna Regina Nakandakare;
Luis Antonio Salazar Navarrete
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| Advisor: | Rosario Dominguez Crespo Hirata |
| Abstract | |
The regulation of cholesterol is mediated by proteins involved in the absorption (NPC1L1), regulation (SREBP1, SREBP2, SCAP), synthesis (HMGCR) and removal of plasma cholesterol (LDLR). Potent hypocholesterolemic agents inhibit cholesterol synthesis (statins) and its absortion (ezetimibe). Changes in several genes have been associated to different responses to various therapeutic agents. In order to evaluate the association between genes involved in the metabolism of cholesterol and their response to lipid lowering drugs, patients with familial (FH, n = 25) and non familial hypercholesterolemia (NHF, n = 72) were selected. Additionally, 125 normolipidemic individuals and without cardiovascular disease were selected (NL). The HF group were treated with simvastatin (40 mg/day/4 weeks) combined or not with ezetimibe (10 mg/day/4weeks). The NHF group were treated with atorvastatin (10 mg/day/4weeks). Blood samples were obtained prior to and following treatment for extraction of DNA and RNA, and serum lipid profile analysis. The mRNA expression of SREBF1a, SREBF2, SCAP, HMGCR, LDLR, and NPC1L1 genes was determined by real time RT-PCR using the GAPD gene as endogenous control. The polymorphisms SREBF1a-36delG, SREBF2 G1784C, and SCAP A2386G were determined by PCR-RFLP. Individuals with HF showed higher expression of mRNA of genes NPC1L1, HMGCR and LDLR when compared with HNF and NL groups (p <0.05). The effect of atorvastatin on the gene expression seems to depend on the baseline expression in HNF subjects. The change of expression after treatment with atorvastatin in group HNF was correlated as followed: SREBF1a and SREBF2; SREBF1a and SCAP; SREBF1a and LDLR; SREBF2 and SCAP; SREBF2 and LDLR; HMGCR and LDLR. Treatment with simvastatin and ezetimibe did not change the gene-expression profile in HF group. The polymorphisms SREBF2 G1784C, and SCAP A2386G appear to be related to a decreased expression of mRNA after treatment with atorvastatin. HNF group Carriers of GG genotype of SREBF2 G1784C polymorphism had higher serum concentrations of total cholesterol and LDL-C after therapy. The SCAP A2386G polymorphism seems to be associated with higher concentrations of apoB in patients from HNF group prior to treatment with atorvastatin. The results suggest that the HMGCR, LDLR and NPC1L1 genes are regulated according to the metabolic status of the individual, and the expression rate of mRNA is influenced by SREBF2 G1784C and SCAP A2386G polymorphisms after atorvastatin therapy. (AU) | |