Elevated leukocyte cell numbers (leukocytosis), and monocytes in particular, promote atherosclerosis; however, how they become increased is poorly understood. Mice deficient in the adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1, which promote cholesterol efflux from macrophages and suppress atherosclerosis in hypercholesterolemic mice, displayed leukocytosis, a transplantable myeloproliferative disorder, and a dramatic expansion of the stem and progenitor cell population containing Lin − Sca-1 + Kit + (LSK) in the bone marrow.

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Hepatic insulin resistance affects both carbohydrate and lipid metabolism. It has been proposed that insulin controls these 2 metabolic branches through distinct signaling pathways. FoxO transcription factors are considered effectors of the pathway regulating hepatic glucose production. Here we show that adenoviral delivery of constitutively nuclear forkhead box O1 (FoxO1) to mouse liver results in steatosis arising from increased triglyceride accumulation and decreased fatty acid oxidation. FoxO1 gain of function paradoxically increased insulin sensitivity by promoting Akt phosphorylation, while FoxO1 inhibition via siRNA decreased it. We show that FoxO1 regulation of Akt phosphorylation does not require DNA binding and is associated with repression of the pseudokinase tribble 3 (Trb3), a modulator of Akt activity. This unexpected dual role of FoxO1 in promoting insulin sensitivity and lipid synthesis in addition to glucose production has the potential to explain the peculiar admixture of insulin resistance and sensitivity that is commonly observed in the metabolic syndrome.

Insulin resistance in diabetes and metabolic syndrome is thought to increase susceptibility to atherosclerotic cardiovascular disease, but the underlying mechanisms are poorly understood. To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. Western diet-fed Insr(-/-) recipients developed larger, more complex lesions with increased necrotic cores and increased numbers of apoptotic cells. Insr(-/-) macrophages showed diminished Akt phosphorylation and an augmented ER stress response, leading to induction of scavenger receptor A and increased apoptosis when challenged with cholesterol loading or nutrient deprivation. These studies suggest that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques.

Background— Two macrophage ABC transporters, ABCA1 and ABCG1, have a major role in promoting cholesterol efflux from macrophages. Peritoneal macrophages deficient in ABCA1, ABCG1, or both show enhanced expression of inflammatory and chemokine genes. This study was undertaken to elucidate the mechanisms and consequences of enhanced inflammatory gene expression in ABC transporter–deficient macrophages. Methods and Results— Basal and lipopolysaccharide-stimulated thioglycollate-elicited peritoneal macrophages showed increased inflammatory gene expression in the order Abca1 −/− Abcg1 −/− > Abcg1 −/− > Abca1 −/− >wild-type. The increased inflammatory gene expression was abolished in macrophages deficient in Toll-like receptor 4 (TLR4) or MyD88/TRIF. TLR4 cell surface concentration was increased in Abca1 −/− Abcg1 −/− > Abcg1 −/− > Abca1 −/− > wild-type macrophages. Treatment of transporter-deficient cells with cyclodextrin reduced and cholesterol-cyclodextrin loading increased inflammatory gene expression. Abca1 −/− Abcg1 − bone marrow–derived macrophages showed enhanced inflammatory gene responses to TLR2, TLR3, and TLR4 ligands. To assess in vivo relevance, we injected intraperitoneally thioglycollate in Abcg1 −/− bone marrow–transplanted, Western diet–fed, Ldlr -deficient mice. This resulted in a profound inflammatory infiltrate in the adventitia and necrotic core region of atherosclerotic lesions, consisting primarily of neutrophils. Conclusions— The results suggest that high-density lipoprotein and apolipoprotein A-1 exert anti-inflammatory effects by promoting cholesterol efflux via ABCG1 and ABCA1 with consequent attenuation of signaling via Toll-like receptors. In response to a peripheral inflammatory stimulus, atherosclerotic lesions containing Abcg1 −/− macrophages experience an inflammatory “echo,” suggesting a possible mechanism of plaque destabilization in subjects with low high-density lipoprotein levels.

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Objective-Recent studies indicate that the ATP-binding cassette transporter ABCG1 can promote cholesterol efflux from macrophages to high-density lipoprotein. This study was designed to assess the in vivo role of macrophage ABCG1 in atherosclerosis. Methods and Results-Bone marrow from Abcg1Ϫ/Ϫ mice was transplanted into irradiated Ldlr Ϫ/Ϫ recipients, and atherosclerosis was evaluated by aortic root assay after 7 or 11 weeks of feeding on a Western diet. After 7 weeks, there was no difference in lesion area in mice receiving either wild-type or Abcg1 Ϫ/Ϫ bone marrow, whereas after 11 weeks, lesion area was moderately but significantly reduced in Abcg1 Ϫ/Ϫ recipients. ABCG1-deficient peritoneal macrophages showed induction of several liver X receptor target genes, such as Abca1 and Srebp1c, and a dramatic increase in apolipoprotein E (apoE) protein both in cell media and lysates, without parallel change in apoE mRNA. Abca1 knockdown prevented the increase in apoE secretion but had minimal effects on apoE accumulation in cell lysates of Abcg1 Ϫ/Ϫ macrophages. Plasma apoE levels were markedly increased in recipients of Abcg1 Ϫ/Ϫ bone marrow. Conclusions-These

Nonstandard abbreviations used: acetylated LDL (acLDL); insulin receptor (IR); IR substrate 2 (IRS-2); LDL receptor (LDLR); oxidized LDL (oxLDL); scavenger receptor A (SR-A); scavenger receptor BI (SR-BI); Tricine-buffered saline (TBS). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionThe complications of atherosclerosis in coronary, cerebral, and peripheral arteries are the major reason for hospital admission in diabetics and account for about 80% of the mortality of this condition (1). Although diabetes is often associated with dyslipidemia (2, 3), the excess risk is disproportionate to lipid abnormalities and the root causes of accelerated atherosclerosis in diabetes are not well understood. Some evidence suggests that insulin resistance, commonly seen in overweight individuals with the metabolic syndrome, is an important cause of both diabetes and increased atherosclerosis risk (4). Insulin resistance has been related to dyslipidemia, hypertension, and hypercoagulability, all factors that may promote atherosclerosis (2, 3). Potentially insulin resistance could also be important at the arterial cellular level (5). Defective insulin signaling in endothelial cells leads to impaired NO activity (6), and this is probably proatherogenic. Macrophages also express insulin receptors (IRs) (7), but the relationship of insulin signaling to macrophage foam cell formation has received little attention. Thiazolidinediones, activators of PPAR-γ, have emerged as an important class of drugs in the treatment of type II diabetes. PPAR-γ activators markedly improve insulin resistance and decrease atherosclerosis in mouse models, and may also decrease atherosclerosis in humans (8-11). Although the in vivo mode of action of PPAR-γ activators is not well understood, PPAR-γ is highly expressed in adipocytes and macrophages (11), suggesting these cells could be important targets. Paradoxically, however, PPAR-γ activators increase the expression of the proatherogenic molecule CD36 in cultured macrophages (12). These proatherogenic effects of PPAR-γ activators may be counteracted by an increase in ABCA1, a macrophage transporter that promotes efflux of cholesterol to lipid-poor apolipoproteins, perhaps offsetting increased uptake of modified low-density lipoprotein (LDL) via CD36 (11,13,14). However, the importance of this mechanism is uncertain, and some studies have failed to find any effect of PPAR-γ activators on ABCA1 levels or lipid efflux in macrophages (15, 16).Obese (ob/ob) mice are genetically deficient in leptin and have been widely used as a model of insulin resistance and diabetes (17). In this study, we made the initial observation that macrophages from ob/ob mice have increased uptake of modified LDL, due to post-transcriptional upregulation of CD36 protein. Unexpectedly, the increase in CD36 is caused by defective insulin signaling in macrophages, suggesting that macrophage insulin resistance promotes foam cell formation. Consistent with this hypothesis, in vivo treatment...