The aim of the present study was to investigate the regulation of the apoAI gene by dietary saturated fat and cholesterol. Saturated fatty acids and cholesterol raise low density- and high density lipoprotein particles in humans. Increased LDL is attributed to the down-regulation of LDL-receptor gene, but the mechanism of increased plasma HDL levels is unknown. To study the mechanism of HDL elevation by saturated fat, male rats and male mice were employed as animal models, since they also raise their plasma HDL levels when fed high lipid diets. Animals were divided in four groups and fed the following diets: control (5% corn oil); high cholesterol (0.5%); high fat (20% coconut oil); and high fat plus cholesterol diets. The high cholesterol diet did not alter plasma and HDL-cholesterol levels. However, the high fat diet increased HDL levels by 20% in rats and 55% in mice. A combination of saturated fat and cholesterol diet raised plasma HDL levels by 36 and 67% in rats and mice, respectively. Plasma apoAI levels increased parallel to HDL concentrations. Mechanism of HDL elevation by saturated fat was investigated. Hepatic and intestinal apoAI mRNA did not change with any of the test diets in mice. Rat hepatic apoAI mRNA was also unchanged by the high cholesterol diet, but was decreased on high fat and fat-cholesterol combination diets. These results suggest that transcriptional regulation of the apoAI gene was not responsible for increased plasma apoAI and HDL. The translational efficiency of apoAI on isolated polysomes was also measured, and it was found that apoAI synthesis increased about 20% on high fat and fat-cholesterol combination diets. This partially explains the elevated levels of plasma HDL. Additional regulation through impaired catabolism of HDL particles by high fat diet feeding may be another pathway for increased HDL levels. Unlike apoAI mRNA, the mRNA of other HDL apoproteins, apoAII and apoAIV, were increased by high fat and combination diet feeding. These results suggest that saturated fatty acids regulate plasma HDL levels by translational and posttranslational mechanisms.