Endogenous apolipoprotein A‐I stabilizes ATP‐binding cassette transporter A1 and modulates Toll‐like receptor 4 signaling in human macrophages

Abstract

Apolipoprotein A-I (ApoA-I) is the main functional protein component of human high-density lipoproteins. ApoA-I shows various anti-inflammatory and atheroprotective properties toward macrophages; however, endogenous apoA-I expression has not been investigated in macrophages. We have shown that endogenous apoA-I gene is expressed in human macrophages at both mRNA and protein levels. Endogenous ApoA-I is localized in intracellular vesicles and at the external side of the plasma membrane in association with ATP-binding cassette transporter A1 (ABCA1) and lipid rafts in macrophages. We have shown that endogenous ApoA-I stabilizes ABCA1, moreover, down-regulation of ApoA-I by siRNA results in an increase of Toll-like receptor 4 (TLR4) mRNA and membrane surface protein expression, as well as an enhancement of bacterial lipopolysaccharide (LPS)-induced expression of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and inducible nitric oxide synthase (NOS2) genes in human macrophages. TNF-α stimulates ApoA-I expression and secretion (1.2±0.2 vs. 4.3±0.9 ng/mg total protein) in macrophages. Obtained results suggest that endogenous ApoA-I has anti-inflammatory properties, presumably due to ABCA1 stabilization in macrophages; these results elucidate the cell type-specific mechanism of the TNF-α-mediated regulation of apoA-I gene expression in monocytes and macrophages.

Macrophages and lipid metabolism

“…Excess free cholesterol in the ER, for example due to impaired efflux, can result in defective re-esterification promoting further accumulation of free cholesterol in the cell, such as at lipid rafts in the membrane [146] . This causes enhanced inflammatory signalling at the membrane lipid rafts including TLR signalling and NFκB activation [146] , [147] , [148] . Inflammatory signalling is further exacerbated if cholesterol trafficking from lysosomes becomes defective.…”

Insulin-Mediated Downregulation of Apolipoprotein A-I Gene in Human Hepatoma Cell Line HepG2: The Role of Interaction Between FOXO1 and LXRβ Transcription Factors

“…ApoA‐I is highly expressed in hepatocytes and these cells together with enterocytes are the main source of plasma ApoA‐I [Higuchi et al, ]. Recently, ApoA‐I synthesis was found in human monocytes and macrophages, where it stabilizes ABCA1 and possesses anti‐inflammatory activity [Mogilenko et al, ]. apoA‐I gene activity is mainly controlled by the hepatic enhancer (HE) located in coordinates −222…−110 relative to the major transcription start point.…”

A network pharmacology-based analysis to distinguish the differences between Lonicerae Japonicae Flos and Lonicerae Flos

“…LJF and LF mainly act in extracellular space, including lysosomes and other cell components, for in ammation. The targets of LJF were located on the external side of plasma membrane, including pivotal proteins with anti-in ammatory properties, such as ApoA-I [29]. The I-κB/NF-κB complex was found to be more relevant to LF than to LJF.…”