Link between hyperhomocysteinaemia, HDL cholesterol and atherosclerosis

Two recent studies1,2 provide evidence for a link between plasma homocysteine, high-density lipoprotein (HDL) cholesterol and cardiovascular disease. Elevated homocysteine levels inhibit synthesis of apolipoprotein A-I (apoA-I), the main HDL apolipoprotein which has atheroprotective effects.

Epidemiological studies have identified elevated homocysteine (hyperhomocysteinaemia) as an independent risk factor for cardiovascular disease. Low HDL cholesterol is also established as a strong predictive factor for cardiovascular disease. Using animal models, scientists have shown that overexpression of apoA-I is associated with raised HDL cholesterol levels and reduced susceptibility to diet-induced atherosclerosis. This suggests that the protective effect of apoA-I may be related to HDL production. Two studies described here investigated the evidence for this.

Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating homocysteine levels. A genetic polymorphism in MTHFR is the most common cause of mild hyperhomocysteinaemia. In one study, researchers used a mouse model deficient in MTHFR (heterozygous for the MTHFR gene, Mthfr+/-), to investigate the effects of mildly elevated homocysteine levels on lipid metabolism. In vitro studies using liver tissue from these mice showed reduced expression of apoA-I and apoA-IV (another apolipoprotein with similar functions to apoA-I). There was also increased expression of cholesterol 7α hydroxylase (Cyp7A1), an enzyme which catalyses the rate-limiting step in the conversion of cholesterol into bile acids in the liver. As a result, apoA-I protein levels in the liver and plasma of these mice were reduced by about 50-60% compared with control mice (Mthfr+/+).

In a second study2, researchers used a mouse model of both hyperhomocysteinaemia and atherosclerosis to investigate the link between homocysteine and HDL. In these mice, hyperhomocysteinaemia reduced levels of apoA-I protein in the plasma and liver, inhibited apoA-I protein synthesis in the liver and increased clearance of HDL cholesteryl esters from plasma. Both studies also showed that plasma homocysteine levels were negatively correlated with both HDL cholesterol and apoA-I levels in cohorts of patients with coronary artery disease.1,2

Taken together, these studies indicate that elevated homocysteine levels reduce HDL cholesterol levels by inhibiting the synthesis of the main apolipoprotein in HDL, apoA-I. The mechanism of this effect is, however, not yet clear. These results may help to explain findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study in which an increase in homocysteine levels with fenofibrate was associated with a less than expected increase in HDL cholesterol levels (less than 2% at study close), as well as reduction in cardiovascular events.

References

1. Mikael LG, Genest J, Rozen R. Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. Circ Res 2006;98:564-71.

2. Liao D, Tan H, Hui R et al. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I protein synthesis and enhancing HDL cholesterol clearance. Circ Res 2006;99:598-606.