Abstract
Elevated levels of lipoprotein(a) [Lp(a)] are an important genetic risk factor for atherosclerotic heart disease. Lp(a) consists of a low-density lipoprotein (LDL) covalently bound to the plasminogen homologue, apolipoprotein(a) [apo(a)]. Enhancing Lp(a) clearance is of interest, however, its catabolism remains poorly understood. The LDL and plasminogen receptors are potential mediators of Lp(a) uptake. While LDL receptor involvement is debated, plasminogen receptors have recently been shown to be promising. Interestingly, serotonin-based antidepressants, like citalopram, have been shown to upregulate plasminogen receptors, enhancing hepatic Lp(a) uptake.
Here, we investigated citalopram’s effect on extra-hepatic Lp(a) uptake, focusing on the kidney due to clinical evidence of renal involvement, and monocytes, given their role in Lp(a) uptake in atherosclerosis. Citalopram’s impact on LDL and HDL uptake in liver and kidney cells was also studied. HepG2, HEK293, and THP-1 cells were treated with 25 or 50 μM citalopram and incubated with human plasma-purified lipoproteins. Lp(a) uptake was measured by western blot, and receptor expression was assessed via confocal microscopy.
Citalopram significantly increased apo(a) and Lp(a) uptake at both 25 μM and 50 μM in HepG2 liver cells. In HEK293 kidney cells, apo(a) uptake remained unchanged with citalopram, whereas Lp(a) treatment displayed significantly decreased uptake at 25 μM (p=7.63 × 10⁻⁵) and 50 μM (p=1.32 × 10⁻⁶). Unlike previous observations in HepG2 cells, citalopram did not alter the expression of plasminogen receptors PlgRKT, AnnexinA2, or S100A10 in HEK293 cells. LDLR expression increased with citalopram, whereas LRP2 expression remained unchanged. A competitive assay revealed substantially reduced HEK293 Lp(a) uptake when LDL was present in a 2-fold excess. Importantly, we found that HEK293 cells only internalised the apo(a) component and not the LDL component despite being treated with intact Lp(a). Yet, competitive inhibition of apo(a) uptake by LDL excess suggests that Lp(a) and LDL share a common receptor, which possibly facilitates cleavage into isolated apo(a) to allow for apo(a) uptake. This, combined with the absence of citalopram-induced plasminogen receptor upregulation, suggests distinct mechanisms of Lp(a) uptake between liver and kidney cells. Apo(a) uptake in THP-1 monocytes appeared unchanged but requires further validation. LDL uptake assessment revealed that citalopram had significantly increased uptake in both cell lines, with LDLR upregulation explaining increased renal uptake (and possibly hepatic uptake). These findings highlight citalopram’s therapeutic potential to lower both Lp(a) and LDL levels. HDL uptake could not be detected in both cell lines. Future experiments will further investigate the involvement of plasminogen receptors in renal apo(a) uptake and possible pathways facilitating renal Lp(a) cleavage.