Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Antidepressants are complex regulators of lipoprotein(a) macropinocytosis Multiple receptors have been implicated in lipoprotein(a) (Lp(a)) uptake, yet each receptor only partially accounts for the uptake, and no endocytic pathway has been described for Lp(a) internalisation to date. In this study, we define macropinocytosis as the endocytic pathway responsible for internalising Lp(a). In liver and macrophage cells, Lp(a) uptake was dependent on extracellular calcium and inhibited by amiloride or its derivative EIPA (5-(N-ethyl-N-isopropyl)-Amiloride). Uptake of the unique protein component of Lp(a), apolipoprotein(a) (apo(a)) alone was also dependent on macropinocytosis, indicating that it is the likely mediator of Lp(a) uptake. In macrophages, the tricyclic antidepressant, imipramine, and the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and sertraline all inhibited Lp(a) uptake, likely due to macrophage de-differentiation effects and dynamin inhibition (in the case of sertraline). In liver cells, imipramine and citalopram strongly stimulated Lp(a) uptake, while sertraline inhibited uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) rather than upregulating macropinocytosis per se, indicating that immobilisation on the plasma membrane is an important step in Lp(a) macropinocytosis. Serotonin treatment also increased Lp(a) cell surface binding, promoting subsequent macropinocytotic uptake, consistent with imipramine and citalopram boosting extracellular serotonin levels through serotonin transporter inhibition. Imipramine and citalopram increased Lp(a) delivery to Rab11-positive recycling endosomes which promoted recycling of the apo(a) component of Lp(a) into the culture media. These findings support the utility of imipramine and citalopram as promising Lp(a)-lowering therapeutics in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.

SummaryElevated lipoprotein(a) (Lp(a)) levels have been found in individuals suffering from depression posing an increased risk of cardiovascular disease (CVD). Efforts to effectively reduce circulating Lp(a) levels have been limited due to an inability to ascribe a clear cellular uptake pathway, despite multiple receptors being implicated in Lp(a) uptake. We report here that Lp(a) uptake is mediated by the fluid-phase endocytic process, macropinocytosis. Furthermore, serotonin and commonly prescribed antidepressants promote Lp(a) uptake by macropinocytosis in liver cells by increasing cell surface association. These findings represent a major paradigm shift in Lp(a) biology since previous studies have attributed Lp(a) uptake to receptor-mediated endocytosis. They also imply that treatment with antidepressants may improve cardiovascular as well as mental health.
15
The categories of this paper are: developmental
18
The categories of this paper are: systems
11
The categories of this paper are: cognition
13
The categories of this paper are: animal
24
The categories of this paper are: cancer
8
The categories of this paper are: genomics
23
The categories of this paper are: immunology
20
The categories of this paper are: pharmacology
0
The categories of this paper are: genetics
22
The categories of this paper are: physiology
10
The categories of this paper are: and
21
The categories of this paper are: toxicology
26
The categories of this paper are: biochemistry
1
The categories of this paper are: bioinformatics
28
The categories of this paper are: communication
6
The categories of this paper are: plant