Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia

Dong, Weilai; Wong, Karen; Liu, Youbin; Levy‐Sakin, Michal; Hung, Wei-Chien; Li, Mo; Li, Boyang; Jin, Sheng; Choi, Jungmin; López-Giráldez, Francesc; Vaka, Dedeepya; Poon, Annie; Chu, Catherine; Lao, Richard; Balamir, Melek; Movsesyan, Irina; Malloy, Mary J.; Zhao, Hongyu; Kwok, Pui‐Yan; Kane, John P.; Lifton, Richard P.; Pullinger, Clive R.

doi:10.1016/j.jlr.2022.100209

Cited by 2 publications

(1 citation statement)

References 86 publications

(109 reference statements)

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“…We recently showed that ABCA7-lipoprotein contains less cholesterol than ABCA1-lipoprotein, likely because of lower cholesterol solubility in the phospholipid bilayer of ABCA7-lipoprotein 2 of 22 than ABCA1-lipoprotein [10]. While common variants at the loci of ABCA1 and ABCA8, another structurally related lipid transporter [11], are associated with plasma cholesterol measures, this is not the case for the variants at the ABCA7 locus, in human populations [12][13][14][15]. Furthermore, disruption of intracellular cholesterol metabolism [16,17], cholesterol depletion [18][19][20] or up-regulation of SREBP-2 [21] affect expression of the genes for ABCA1 and ABCA8 but not ABCA7 in many tissues.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA

Wiener,

Desire,

Garliyev

et al. 2023

Cells

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Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) is a major risk factor for Alzheimer’s disease. Human neural cell lines were used to investigate the regulation of ABCA7 expression by cholesterol and pro-inflammatory cytokines. Cholesterol was depleted by methyl-β-cyclodextrin, followed by treatment with rosuvastatin to suppress de novo synthesis, while the cells underwent adjustment to low cholesterol. Cholesterol depletion by 50–76% decreased ABCA7 expression by ~40% in C20 microglia and ~21% in A172 astrocytes but had no effect on the protein in SK-N-SH neurons. Cholesterol depletion also suppressed ABCA7 in HMC3 microglia. Previously, cholesterol loss was reported to up-regulate ABCA7 in murine macrophages. ABCA7 was down-regulated during PMA-induced differentiation of human THP-1 monocytes to macrophages. But, cholesterol depletion in THP-1 macrophages by ~71% had no effect on ABCA7. IL-1β and TNFα reduced ABCA7 expression in C20 and HMC3 microglia but not in A172 astrocytes or SK-N-SH neurons. IL-6 did not affect ABCA7 in the neural cells. These findings suggest that ABCA7 is active in regular homeostasis in human neural cells, is regulated by cholesterol in a cell type-dependent manner, i.e., cholesterol depletion down-regulates it in human neuroglia but not neurons, and is incompatible with IL-1β and TNFα inflammatory responses in human microglia.

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