Abstract Or122: SURF4-containing Classical Vesicles Mediate Apolipoprotein(a)-ApolipoproteinB Secretory Trafficking
Abstract
Introduction:
Elevated plasma levels of Lp(a) are an independent, causal risk factor for cardiovascular diseases. Plasma Lp(a) concentration depends mainly on Lp(a) production rate in hepatocytes, which is mediated by intracellular non-covalent complexes between weak lysine binding sites in apo(a) kringles IV types 7 and 8 (LBS7,8) with apoB. Lp(a) is smaller, denser and more cholesterol-rich than VLDL, and Lp(a)-apoB is secreted at a lower rate than VLDL-apoB. Thus, Lp(a) and VLDL may follow different intracellular assembly and trafficking pathways. VLDL secretory trafficking has been reported to involve SURF4-containing, TANGO1-dependent, expanded COPII VLDL transport vesicles (VTV). However, the mechanisms causing differences in lipidation and apolipoprotein composition of Lp(a) compared to VLDL remain unclear.
Hypothesis:
The intracellular interaction between apo(a) and apoB diverts nascent Lp(a) from VTVs and hence impacts its secretion rate and lipidation.
Methods:
HuH7 cells were transfected with plasmids encoding either 17K (wild-type) or 17K△LBS7,8 apo(a) and incubated with oleic acid to stimulate lipoprotein assembly. Lp(a) secretion was assessed by immunoblot of medium from cells also transfected with siRNAs targeting expression of the VLDL-associated proteins SURF4, TM6SF2, FITM2, MTP or TANGO1. Interactions between apo(a), apoB and the VLDL ER cargo receptor, SURF4 were studied by pulldown assays. Confocal and super resolution radial fluctuation (SRRF)…
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