Docosahexanoic acid modifies low-density lipoprotein receptor abundance in HepG2 cells via suppression of the LXRα-Idol pathway

As a daily supplement, omega-3 fatty acid is confirmed to be of benefit in hypertriglyceridemia. However, the effect of omega-3 fatty acids on the low-density lipoprotein cholesterol (LDL-C) metabolism remains a controversial issue. In this study, we focused on the regulatory effect of docosahexanoic acid (DHA), one type of omega-3 fatty acid, exerted on the LDL receptor (LDLR), a determinant regulator of the LDL-C metabolism, and explored the potential mechanism. We observed that DHA increased hepatic LDLR protein in the presence of 25-hydroxycholesterol in HepG2 cells but did not alter the mRNA level. Previous studies have identified inducible degrader of the LDLR (Idol) as a novel negative post-translational modulator of LDLR and a direct transcriptional target of liver X receptor a (LXR alpha). Since DHA had no effect on the transcriptional level of LDLR, we speculated that the post-transcriptional pathway LXR alpha-Idol participated in this regulation. The results reveal that DHA downregulated the expression of LXR alpha and Idol in coordination with the upregulation of LDLR expression. Multiple mechanisms are involved in the regulation of LDLR by DHA, and the suppression of the LXR alpha-Idol pathway is one of these mechanisms.