Effect of experimental hyperhomocysteinemia on plasma lipid profile, insulin sensitivity and paraoxonase 1 in the rat

Hyperhomocysteinemia (hHcy) is a well-known risk factor of cardiovascular diseases, however, the mechanism of its detrimental effect is incompletely understood. Some studies suggest that, paradoxically, hHcy may promote traditional risk factors such as hyperlipidemia. We examined the effect of experimental hHcy on plasma lipid profile, glucose and insulin concentrations as well as on high-density lipoprotein (HDL)-associated antiatherosclerotic enzyme, paraoxonase 1 (PON1). Hyperhomocysteinemia was induced by feeding male Wistar rats with diet enriched with methionine or diet enriched in methionine and deficient in folate, vitamin B6 and B12 for 8 weeks. These diets resulted in the 3.3- and 9.6-fold elevation of plasma Hcy, respectively. Plasma total and HDL-cholesterol, triglycerides and apolipoprotein A-I were similar in all groups. High-methionine diets had no effect on fasting plasma glucose but significantly increased fasting plasma insulin concentration indicating impaired ability of insulin to suppress hepatic glucose output. PON1 activity was unchanged in high methionine vitamin B-sufficient diet-fed rats, but was decreased by 30-40% toward various substrates in high methionine vitamin B-deficient diet-fed animals. The results indicate that hHcy has no effect on lipid metabolism, however, induces insulin resistance and, above certain Hcy level, PON1 deficiency. Impaired insulin signaling and reduced PON1 activity may contribute to detrimental effects of hHcy. Adipobiology 2012; 4: 77-84.