Increased Cellular Free Cholesterol in Macrophage-specific Abca1 Knock-out Mice Enhances Pro-inflammatory Response of Macrophages

Abstract

Macrophage-specific Abca1 knock-out (Abca1؊M/؊M ) mice were generated to determine the role of macrophage ABCA1 expression in plasma lipoprotein concentrations and the innate immune response of macrophages. Plasma lipid and lipoprotein concentrations in chow-fed Abca1 ؊M/؊M and wild-type (WT) mice were indistinguishable. Compared with WT macrophages, Abca1 ؊M/؊M macrophages had a >95% reduction in ABCA1 protein, failed to efflux lipid to apoA-I, and had a significant increase in free cholesterol (FC) and membrane lipid rafts without induction of endoplasmic reticulum stress. Lipopolysaccharide (LPS)-treated Abca1 ABCA1 (ATP-binding cassette transporter A1) is a plasma membrane protein that is widely expressed throughout the body (1, 2) and functions as a primary gatekeeper for eliminating excess free cholesterol (FC) 2 from tissues by effluxing cellular FC and phospholipid (PL) to lipid-free apoA-I, resulting in the formation of nascent high density lipoprotein (HDL) particles (3, 4). The nascent discoid-shaped HDL then undergoes a maturation process that involves additional lipid acquisition and conversion of FC to cholesteryl ester (CE) by lecithin:cholesterol acyltransferase to become mature spherical plasma HDL. Mutations that inactivate the human ABCA1 gene result in Tangier disease, which is characterized by extremely low HDL cholesterol concentrations, mildly elevated plasma trigelyceride levels, and accumulation of cholesterol in macrophages (5-10). Targeted deletion of Abca1 in mice and a natural mutation of Abca1 in the Wisconsin hypoalpha mutant chicken recapitulate the Tangier plasma lipid phenotype, supporting the essential role of ABCA1 in HDL formation (11-15). Although ABCA1 is expressed in many cells in the body, recent studies in hepatocyte-and intestinal epithelium-specific Abca1 knock-out mice suggest that the liver contributes 70 -80% of the plasma HDL pool, whereas the intestine contributes 20 -30% (16, 17). Although mobilization of excess FC from macrophages is dependent on ABCA1 and results in the formation of nascent HDL particles, transplantation of bone marrow from Abca1 knock-out (KO) mice into wild-type (WT) mice or transplantation of WT marrow into Abca1 KO recipients has little effect on plasma HDL concentrations, suggesting that macrophage ABCA1 expression has minimal impact on plasma HDL concentrations (18,19).Macrophages are a primary cell type involved in innate immunity. Although macrophage ABCA1 has a minimal impact on plasma lipid levels, there is evidence that its activity modulates the inflammatory response of macrophages to pathogen-associated molecules such as lipopolysaccharide

Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1

“…Suppression of inflammatory cytokine secretion by st-Ht31 is not entirely unexpected, because depleting cellular cholesterol by MCD is known to have similar effects (25). However, MCD removes cholesterol indiscriminately and suppresses inflammatory responses independent of ABCA1 expression (25).…”

“…However, MCD removes cholesterol indiscriminately and suppresses inflammatory responses independent of ABCA1 expression (25). This could potentially suppress constructive inflammatory responses aimed to restore tissue homeostasis.…”

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

“…Real-time PCR Analysis-Total RNA was isolated from liver of age-matched male mice using TRIzol (Invitrogen), and realtime PCR was performed as described previously (23). Primer sequences for ABCA1, ABCG1, SRBI, SREBP2, LXR␣, LXR␤, and GAPDH expression were the same as reported previously (23).…”

“…Primer sequences for ABCA1, ABCG1, SRBI, SREBP2, LXR␣, LXR␤, and GAPDH expression were the same as reported previously (23). Sequences for ABCG5, LRP, LDLr, SREBP1c, PPAR␣, PPAR␥, PGC1␣, and FXR␣ are summarized in supplemental Table 1.…”

The Role of Altered Lipid Metabolism in Septic Myocardial Dysfunction

“…Also the endothelial function is modified through an increased production of nitric oxide (NO) by the stimulation of endothelial nitric oxide synthase (eNOS) mediated by the activation of the protective PI3K\Akt pathway leading to vasodilation, antiadhesion and anti-inflammatory effects [107]. A similar cardioprotective and antiapoptotic action of HDL have been shown through the activation of Stat3 mediated by sphingosine 1 phosphate (S1P), one of their common component [108].…”