Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.5.7.1 (
methylenetetrahydrofolate reductase
)
2,116
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in
methylenetetrahydrofolate reductase
(
MTHFR
) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism. Microarrays and RT-PCR showed decreased mRNA for apolipoprotein A (ApoA)-IV and for
ApoA-I
and increased mRNA for cholesterol 7alpha hydroxylase (Cyp7A1) in Mthfr(+/-) mice compared with Mthfr(+/+) mice. Western blotting revealed that
ApoA-I
protein levels in liver and plasma of Mthfr(+/-) mice were 52% and 62% of levels in the respective tissues of Mthfr(+/+) mice. We also performed Western analysis for plasma
ApoA-I
protein levels in 60 males with coronary artery disease and identified a significant (P<0.01) negative correlation (-0.33) between
ApoA-I
and plasma homocysteine levels. This cohort also displayed a negative correlation (-0.24, P=0.06) between high-density lipoprotein cholesterol and plasma homocysteine. Treatment of HepG2 cells with supraphysiological levels of 5 mmol/L homocysteine reduced peroxisome proliferator-activated receptor (PPAR) alpha and
ApoA-I
protein levels and decreased
ApoA-I
promoter activity. Transfection with a PPARalpha construct upregulated
ApoA-I
and
MTHFR
. Our results suggest that hyperhomocysteinemia may increase risk of atherosclerosis by decreasing expression of
ApoA-I
and increasing expression of CYP7A1.
...
PMID:Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. 1651 70
