Differential regulation of LDL receptor (LDLr) gene expression by fatty acids in fibroblasts

In the present study, we examined the effect of different fatty acids (FAs) on regulation of LDLr gene expression in human skin fibroblasts When fibroblasts were cultured with serum free DMEM for 48 h there was a 3- to 6-fold increase in LDLr mRNA and a 2-fold increase in LDLr protein levels. Incubation of fibroblasts with 5 μg/ml of 25-OH cholesterol (25-OH) for 24 h decreased LDLr mRNA by 80-90% and LDLr protein by 70-80%. When fibroblasts were cultured with 25-OH and individual FAs (0.25-0.75 mM), gene expression was affected in different ways that depended upon the FA studied. Myristic acid (14:0), AA (20:4), and EPA (20:5) antagonized the depression of LDLr gene expression by 25-OH; both LDLr mRNA and protein levels were increased by 40-70% vs those observed in the presence of 25-OH. In contrast, DHA and linoleic acid (18:2) further decreased LDLr mRNA by 10-20% and LDLr protein by 20-25% beyond the suppression observed in the presence of 25-OH In the presence of FAs alone, 14:0, AA, and EPA increased LDLr protein and mRNA levels by 10-30%, whereas DHA and 18:2 decreased these by 20-60%. The results suggest that FAs have different regulatory effects on LDLr gene expression and that the mechanisms by which this occurs for certain FAs (i.e. 18:2 & DHA) differ from those that mediate the effects of 25-OH on LDLr gene expression.