Apolipoprotein AI and High-Density Lipoprotein Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters

Abstract

Rationale Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species (ROS) and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids (SFAs) such as palmitate occurs via translocation of NADPH oxidase 4 (NOX4) into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein A-I (apoA-I) and HDL on macrophages and endothelial cells appears to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoA-I on adipocytes. Objective To determine whether apoA-I and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs. Methods and Results In 3T3L-1 adipocytes, apoA-I, HDL and methyl-β-cyclodextrin inhibited chemotactic factor expression. ApoA-I and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NOX4 translocation into LRs, and reduced palmitate-induced ROS generation and monocyte chemotactic factor expression. Silencing ABCA-1 abrogated the effect of apoA-I, but not HDL, while silencing ABCG-1 or SRB-1 abrogated the effect of HDL but not apoA-I. In vivo, apoA-I transgenic mice fed a high fat, high sucrose, cholesterol-containing diet showed reduced chemotactic factor and pro-inflammatory cytokine expression and reduced macrophage accumulation in adipose tissue. Conclusion ApoA-I and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters such as ABCA-1, ABCG-1 and SRB-1.

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

“…Lipid rafts in differentiated adipocytes was detected following incubation with 1 mg/mL Alexa Fluor 594-conjugated cholera toxin subunit-b (Molecular Probes) for 15 min at 4°C, as previously described (4,6). Indeed, binding of cholera toxin subunit-b to the pentasaccharide chain of plasma membrane ganglioside G M1 , which selectively partitions into lipid rafts (18), allows the reliable detection of lipid rafts in live cells.…”

“…ABCG1 is expressed in adipocytes and in adipose tissue of mice that develop diet-induced obesity (5,6). Moreover, adipose tissue is a major source of LPL (7), which critically controls TG accumulation by generating free fatty acids from circulating lipoproteins (8).…”

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

“…In this regard, activation of the PI3K/AKT pathway by SR-B1 ligands provides an essential survival signal for tumor cells [84,85]. A third mechanism of SR-B1 to promote tumor growth is by the inhibition of acute inflammation [73,74]. SR-B1 has been implicated in several biological processes such as apoptosis [86,87] entry through TRPC3 channels, leading to dampened cytokine production in response to CpG via TLR9 activation [90].…”

HDLs, Diabetes, and Metabolic Syndrome

“…ApoA-I and HDL have been shown to have antiinflammatory properties in adipocytes similarly to what has been observed in macrophages and endothelial cells. It was found that both HDL and ApoA-I inhibit palmitate-mediated gene induction of pro-inflammatory chemotactic factor (e.g., monocyte chemotactic protein-1, serum amyloid A3) in cultured adipocytes (Umemoto et al 2013). Furthermore, there was a reduction in chemotactic factor expression and macrophage accumulation in ApoA-I transgenic mice fed a high-fat diet compared to similarly treated control mice (Umemoto et al 2013).…”

“…It was found that both HDL and ApoA-I inhibit palmitate-mediated gene induction of pro-inflammatory chemotactic factor (e.g., monocyte chemotactic protein-1, serum amyloid A3) in cultured adipocytes (Umemoto et al 2013). Furthermore, there was a reduction in chemotactic factor expression and macrophage accumulation in ApoA-I transgenic mice fed a high-fat diet compared to similarly treated control mice (Umemoto et al 2013). Because macrophage accumulation and adipose tissue inflammation are strongly correlated with insulin resistance, these observations provide potential implications for the prevention and management of insulin resistance.…”