Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase...

Hyperhomocysteinemia (HHcy) can result from genetic or nutritional disturbances in folate metabolism. The most common genetic cause of mild HHcy is methylenetetrahydrofolate reductase (MTHFR) deficiency. To explore interactions between HHcy and lipid metabolism in atherogenesis, we measured plasma homocysteine (Hcy), triglycerides and cholesterol in Mthfr(+/+) and Mthfr(+/-) mice on C57BL/6 and BALB/c backgrounds, fed control or folate-deficient diets. We also crossed ApoE(C57)(-/-) mice with Mthfr(C57)(+/-) and Mthfr(BALB/c)(+/-) mice, and examined the same plasma variables as well as lipid accumulation in aortic sinus and whole aorta. Mthfr(+/-) mice had significantly higher plasma Hcy and plasma triglycerides relative to Mthfr(+/+) mice. A significant positive correlation was observed between plasma Hcy and plasma triglycerides in all mice. Mthfr(+/-) mice had lower plasma ApoA-IV protein levels which could reduce clearance of triglyceride-rich lipoproteins from the circulation. In the double mutant experiments, plasma Hcy was higher in Mthfr(+/-) compared with Mthfr(+/+) in ApoE(C57)(-/-)/Mthfr(C57) and ApoE(C57)(-/-)/Mthfr(BALB/c) mice. Triglycerides in female ApoE(C57)(-/-)/Mthfr(BALB/c)(+/-) mice were higher than those in ApoE(C57)(-/-)/Mthfr(BALB/c)(+/-) mice and correlated positively with Hcy. ApoE(C57)(-/-)/Mthfr(C57)(+/-) male mice had more lipid deposition in aortic sinus and whole aorta compared with ApoE(C57)(-/-)/Mthfr(c57)(+/+) mice. Our results suggest that HHcy is associated with hypertriglyceridemia and that MTHFR deficiency may exacerbate lipid accumulation in ApoE deficiency.