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2018 ; 38
(7
): 1504-1518
Nephropedia Template TP
Jin X
; Dimitriadis EK
; Liu Y
; Combs CA
; Chang J
; Varsano N
; Stempinski E
; Flores R
; Jackson SN
; Muller L
; Woods AS
; Addadi L
; Kruth HS
Arterioscler Thromb Vasc Biol
2018[Jul]; 38
(7
): 1504-1518
PMID29853567
show ga
OBJECTIVE: Cells use various mechanisms to maintain cellular cholesterol
homeostasis including efflux of cholesterol from the cellular plasma membrane to
cholesterol acceptors such as HDLs (high-density lipoproteins). Little is known
about the transfer of cholesterol from cells into the extracellular matrix. Using
a unique monoclonal antibody that detects ordered cholesterol arrays (ie,
cholesterol micro[or nano]-domains), we previously identified that particles
containing these cholesterol domains accumulate in the extracellular matrix
during cholesterol enrichment of human monocyte-derived macrophages and are found
in atherosclerotic lesions. In this study, we further investigate these deposited
particles containing cholesterol microdomains and discover their unexpected
morphology. APPROACH AND RESULTS: Although appearing spherical at the resolution
of the conventional fluorescence microscope, super-resolution immunofluorescence
and atomic force microscopy of in situ cholesterol microdomains, and
immunoelectron microscopy of isolated cholesterol microdomains revealed that the
microdomains are not vesicles or 3-dimensional crystals but rather appear as
branching irregularly shaped deposits of varying size. These cholesterol
microdomain-containing deposits are shed from the plasma membrane into the
extracellular matrix. CONCLUSIONS: To date, research on cellular excretion of
excess cholesterol has demonstrated cellular cholesterol efflux in the form of
membranous vesicles and discoidal HDL particles released into the fluid-phase
medium. Shedding of plasma membrane cholesterol microdomains provides an
additional mechanism for cells such as macrophages to maintain plasma membrane
cholesterol homeostasis. Furthermore, recognition that macrophages shed
cholesterol microdomains into the extracellular matrix is important to our
understanding of extracellular buildup of cholesterol in atherosclerosis.