Abstract
Elevated levels of lipoprotein (a) [Lp(a)] are a well-established risk factor for developing CVD. While Lp(a) levels are thought to be independent of other plasma lipoproteins, some trials have reported a positive association between Lp(a) and HDL. Whether Lp(a) has a direct effect on HDL is not known. Here we investigated to determine whether Lp(a) had any effect on the ABCA1 pathway of HDL production in liver cells. Incubation of HepG2 cells with Lp(a) upregulated the PPARγ protein by 1.7-fold and the liver X receptor α protein by 3-fold. This was accompanied by a 1.8-fold increase in ABCA1 protein and a 1.5-fold increase in cholesterol efflux onto apoA1. We showed that Lp(a) was internalized by HepG2 cells, however, the ABCA1 response to Lp(a) was mediated by the selective uptake of oxidized phospholipids (oxPLs) from Lp(a) via the scavenger receptor-B1 and not by Lp(a) internalization per se. We conclude that there is a biological connection between Lp(a) and HDL through the ability of Lp(a)’s oxPLs to upregulate HDL biosynthesis.
Highlights
Elevated levels of lipoprotein (a) [Lp(a)] are a wellestablished risk factor for developing CVD
Our results showed that Lp(a) stimulates ABCA1 via activation of PPAR␥ and liver X receptor (LXR)␣ resulting in a functional effect of enhanced cholesterol efflux to apoA1
Treatment of HepG2 cells with LDL stimulated ABCA1 expression, but not to the extent seen by Lp(a) and not in a concentrationdependent manner with ABCA1 protein levels, showing a 1.2-fold increase at 1, 5, and 10 g/ml (Fig. 1C)
Summary
Elevated levels of lipoprotein (a) [Lp(a)] are a wellestablished risk factor for developing CVD. Incubation of HepG2 cells with Lp(a) upregulated the PPAR␥ protein by 1.7-fold and the liver X receptor ␣ protein by 3-fold This was accompanied by a 1.8-fold increase in ABCA1 protein and a 1.5-fold increase in cholesterol efflux onto apoA1. We showed that Lp(a) was internalized by HepG2 cells, the ABCA1 response to Lp(a) was mediated by the selective uptake of oxidized phospholipids (oxPLs) from Lp(a) via the scavenger receptor-B1 and not by Lp(a) internalization per se. Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids. PPAR␥ and LXR␣ promote ABCA1-mediated cholesterol efflux to stimulate HDL formation [6,7,8]. Past studies have shown that LDL induces ABCA1-mediated cholesterol efflux in both macrophage [16] and endothelial cells [17].
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