Regulation of gene expression by dietary fatty acids in cholesterol metabolism

Regulatory mechanisms responsible for the variable effects of dietary fatty acids on cholesterol metabolism were investigated. Male Syrian hamsters (F1B hybrid) were fed a modified version of the NIH-07 open formula, cereal-based rodent diet enriched in one of five dietary fatty acids: palmitic acid, stearic acid, 18:1trans fatty acids (TFA), oleic acid, or linoleic acid. Dietary palmitic acid and TFA significantly (P \u3c 0.05) increased plasma cholesterol concentration compared to the other groups. TFA also caused an increase in plasma triacylglycerol and apolipoprotein B100 concentration compared to the other groups (P \u3c 0.05). In the liver, free cholesterol concentration was significantly higher in the TFA group compared to hamsters fed stearic acid. Hepatic cholesteryl ester concentration was significantly higher in hamsters fed oleic acid and linoleic acid. Hepatic acyl-coA:cholesterol acyltransferase (ACAT) activity was significantly higher in the palmitic acid and stearic acid groups compared to the others. However, there was no significant difference in hepatic ACAT-1 and ACAT-2 mRNA levels, suggesting ACAT activity may be regulated by fatty acids at the posttranscriptional level. ACAT-1 was expressed in all the tissues examined; in contrast, ACAT-2 was mainly expressed in the liver and small intestine, implying that ACAT-2 may be involved in lipoprotein production by these tissues. Palmitic acid significantly reduced hepatic cytosolic cholesteryl ester hydrolase mRNA levels. ATP-binding cassette transporter G5 (ABCG5) and G8 (ABCG8) were mainly expressed in the liver and small intestine, also suggesting their involvement in lipoprotein production. Hepatic ABCG5 and ABCG8 mRNA levels were significantly higher in hamsters fed TFA and linoleic acid compared to stearic acid. These data demonstrate that individual dietary fatty acids influence hepatic cholesterol metabolism through different mechanisms controlled at the gene level. Moreover, the data suggest that the well-known hypercholesterolemic effect of palmitic acid and TFA is due to increased lipoprotein production by the liver, although inhibition of LDL receptor activity cannot be ruled out. Conversely, dietary stearic acid appears to reduce hepatic lipoprotein production