Abstract
High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway.
Highlights
High density lipoproteins (HDL) is a multi-functional particle that participates in a variety of athero-protective roles that include promotion of endothelial homeostasis and inhibition of monocyte adhesion
Our data revealed that acrolein modification of HDL: (i) impairs the ability of HDL to serve as an acceptor of free cholesterol (FC) from cells and (ii) reduces the efficiency of scavenger receptor class B type I (SR-BI)-mediated HDL-cholesteryl esters (CE) selective uptake
The current report is one of the only to investigate how acrolein impairs HDL function as it pertains to processes related to reverse cholesterol transport, and significantly builds on available literature that only reports the effects of acrolein modification on lipid-free apoA-I function
Summary
HDL is a multi-functional particle that participates in a variety of athero-protective roles that include promotion of endothelial homeostasis and inhibition of monocyte adhesion (reviewed in [1]). SR-BI is highly expressed in the liver and steroidogenic tissues [4,11], and is present in macrophages where it has been suggested to play a role in free cholesterol (FC) efflux to HDL particles [12]. HDL is susceptible to modification by a large cohort of oxidants present in vivo (reviewed in [18]), such as metal ions [19,20], reactive aldehydes [19,21,22,23], and other products of endogenous oxidants [24,25], as well as environmental factors, such as poor diet and tobacco use [26,27] These modifications to HDL may reduce or eliminate HDL’s athero-protective effects, leading to a “dysfunctional” particle (reviewed in [28,29]). We have designed experiments to test our hypothesis that acro-HDL compromises HDL functions to generate a dysfunctional HDL particle that is unable to perform its athero-protective cholesterol-transport functions
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