HDL and apoA-I exhibit an antiinflammatory effect on human monocytes by inhibiting activation of CD11b. ApoA-I acts through ABCA1, whereas HDL may act through several receptors.

Background-Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Methods and Results-Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDLϭϪ2.6Ϯ0.4; placeboϭϪ2.1Ϯ0.3mmol/L; Pϭ0.018). rHDL increased plasma insulin (at 4 hours rHDLϭ3.4Ϯ10.0; placeboϭ Ϫ19.2Ϯ7.4 pmol/L; Pϭ0.034) and also the homeostasis model assessment ␤-cell function index (at 4 hours rHDLϭ18.9Ϯ5.9; placeboϭ8.6Ϯ4.4%; Pϭ0.025). Acetyl-CoA carboxylase ␤ phosphorylation in skeletal muscle biopsies was increased by 1.7Ϯ0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177Ϯ12% and 144Ϯ18%, respectively; PϽ0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (nϭ5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. Conclusions-rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus. Key Words: glucose Ⅲ insulin Ⅲ lipoproteins Ⅲ metabolism Ⅲ muscles H igh-density lipoprotein (HDL) is associated with protection from adverse cardiovascular outcomes in large epidemiological trials. 1 Type 2 diabetes mellitus and the cluster of pathologies including glucose intolerance/insulin resistance, obesity, and high plasma triglycerides that constitute the metabolic syndrome are associated with low and dysfunctional HDL. 2,3 In contrast, aerobically trained individuals have high HDL and display enhanced glucose tolerance. 4 Although the mechanisms linking low HDL to atherosclerosis are well characterized, the links between low HDL and disordered energy metabolism remain relatively unexplored. Given the high and escalating prevalence of type 2 diabetes mellitus, obesity, and the metabolic syndrome and the associated marked elevation in cardiovascular morbidity and mortality, this is an important area of investigation. Clinical Perspective p 2111Recent cell-based studies suggest that HDL may modulate plasma glucose through both insulin-dependent 5,6 and -independent mechanisms. 7 The ATP-binding cassette transporter A1 (ABCA1) has been shown to modulate insulin secretion, 6 and HDL can reverse ...

Several steps of HIV-1 replication critically depend on cholesterol. HIV infection is associated with profound changes in lipid and lipoprotein metabolism and an increased risk of coronary artery disease. Whereas numerous studies have investigated the role of anti-HIV drugs in lipodystrophy and dyslipidemia, the effects of HIV infection on cellular cholesterol metabolism remain uncharacterized. Here, we demonstrate that HIV-1 impairs ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux from human macrophages, a condition previously shown to be highly atherogenic. In HIV-1–infected cells, this effect was mediated by Nef. Transfection of murine macrophages with Nef impaired cholesterol efflux from these cells. At least two mechanisms were found to be responsible for this phenomenon: first, HIV infection and transfection with Nef induced post-transcriptional down-regulation of ABCA1; and second, Nef caused redistribution of ABCA1 to the plasma membrane and inhibited internalization of apolipoprotein A-I. Binding of Nef to ABCA1 was required for down-regulation and redistribution of ABCA1. HIV-infected and Nef-transfected macrophages accumulated substantial amounts of lipids, thus resembling foam cells. The contribution of HIV-infected macrophages to the pathogenesis of atherosclerosis was supported by the presence of HIV-positive foam cells in atherosclerotic plaques of HIV-infected patients. Stimulation of cholesterol efflux from macrophages significantly reduced infectivity of the virions produced by these cells, and this effect correlated with a decreased amount of virion-associated cholesterol, suggesting that impairment of cholesterol efflux is essential to ensure proper cholesterol content in nascent HIV particles. These results reveal a previously unrecognized dysregulation of intracellular lipid metabolism in HIV-infected macrophages and identify Nef and ABCA1 as the key players responsible for this effect. Our findings have implications for pathogenesis of both HIV disease and atherosclerosis, because they reveal the role of cholesterol efflux impairment in HIV infectivity and suggest a possible mechanism by which HIV infection of macrophages may contribute to increased risk of atherosclerosis in HIV-infected patients.

Abstract-Studies have shown a reduction in plaque volume and change in plaque ultrasound characteristics after 4 infusions of reconstituted high-density lipoprotein (rHDL). Whether rHDL infusion leads to acute changes in plaque characteristics in humans is not known. Patients with claudication scheduled for percutaneous superficial femoral artery revascularization were randomized to receive 1 intravenous infusion of either placebo or rHDL (80 mg/kg given over 4 hours). Five to 7 days following the infusion, patients returned and revascularization was performed including atherectomy to excise plaque from the superficial femoral artery. Twenty patients (17 males) average age, 68Ϯ10 years (meanϮSD) were recruited. Eleven patients had a history of documented coronary artery disease, all patients were on aspirin, and 18 were on statins. Ten of the patients received rHDL and 10 placebo. There was significantly less vascular cell adhesion molecule-1 expression (28Ϯ3% versus 50Ϯ3%; PϽ0.05) and a reduction in lipid content in the plaque of HDL-treated subjects compared to placebo. The level of HDL cholesterol increased by 20% after infusion of rHDL and the capacity of apolipoprotein B-depleted plasma to support cholesterol efflux increased. Intravenous infusion of a single dose of reconstituted HDL led to acute changes in plaque characteristics with a reduction in lipid content, macrophage size, and measures of inflammation. These changes may contribute to the cardioprotective effects of HDL.

HIV-infected individuals are at increased risk of coronary artery disease (CAD) with underlying mechanisms including chronic immune activation and inflammation secondary to HIV-induced microbial translocation and low-grade endotoxemia; direct effects of HIV and viral proteins on macrophage cholesterol metabolism; and dyslipidemia related to HIV infection and specific antiretroviral therapies. Monocytes are the precursors of the lipid-laden foam cells within the atherosclerotic plaque and produce high levels of proinflammatory cytokines such as IL-6. The minor CD14+/CD16+ "proinflammatory" monocyte subpopulation is preferentially susceptible to HIV infection and may play a critical role in the pathogenesis of HIV-related CAD. In this review, the central role of monocytes/macrophages in HIV-related CAD and the importance of inflammation and cholesterol metabolism are discussed.

HIV infection has a profound effect on “bystander” cells causing metabolic co-morbidities. This may be mediated by exosomes secreted by HIV-infected cells and containing viral factors. Here we show that exosomes containing HIV-1 protein Nef (exNef) are rapidly taken up by macrophages releasing Nef into the cell interior. This caused down-regulation of ABCA1, reduction of cholesterol efflux and sharp elevation of the abundance of lipid rafts through reduced activation of small GTPase Cdc42 and decreased actin polymerization. Changes in rafts led to re-localization of TLR4 and TREM-1 to rafts, phosphorylation of ERK1/2, activation of NLRP3 inflammasome, and increased secretion of pro-inflammatory cytokines. The effects of exNef on lipid rafts and on inflammation were reversed by overexpression of a constitutively active mutant of Cdc42. Similar effects were observed in macrophages treated with exosomes produced by HIV-infected cells or isolated from plasma of HIV-infected subjects, but not with exosomes from cells and subjects infected with ΔNef-HIV or uninfected subjects. Mice injected with exNef exhibited monocytosis, reduced ABCA1 in macrophages, increased raft abundance in monocytes and augmented inflammation. Thus, Nef-containing exosomes potentiated pro-inflammatory response by inducing changes in cholesterol metabolism and reorganizing lipid rafts. These mechanisms may contribute to HIV-associated metabolic co-morbidities.

This article is available online at http://www.jlr.org Supplementary key words cholesterol metabolism • cholesterol traffi cking • ATP binding cassette transporter A1 • human immunodeficiency virus Impairment of cholesterol metabolism plays a key role in pathogenesis of many disorders, most importantly cardiovascular and neurodegenerative diseases. Many infectious agents, from prions to parasites, affect cholesterol metabolism of the host. Microorganisms modify host cholesterol metabolism for two main reasons: to satisfy their own requirements for cholesterol at different stages of their life cycle, and to weaken the immune response of the host. These modifi cations may cause "unintended" consequences, triggering development of diseases that are not directly related to infection. This situation is exemplifi ed by the increased risk of atherosclerosis coincident with HIV infection. Targeting cholesterol metabolism for antimicrobial intervention, while at the same time correcting metabolic consequences of the infection, is a tempting possibility limited by the lack of knowledge about mechanisms of interaction between microorganisms and pathways of cholesterol metabolism in host cells.

Harlequin Ichthyosis (HI) is a severe and often lethal hyperkeratotic skin disease caused by mutations in the ABCA12 transport protein. In keratinocytes, ABCA12 is thought to regulate the transfer of lipids into small intracellular trafficking vesicles known as lamellar bodies. However, the nature and scope of this regulation remains unclear. As part of an original recessive mouse ENU mutagenesis screen, we have identified and characterised an animal model of HI and showed that it displays many of the hallmarks of the disease including hyperkeratosis, loss of barrier function, and defects in lipid homeostasis. We have used this model to follow disease progression in utero and present evidence that loss of Abca12 function leads to premature differentiation of basal keratinocytes. A comprehensive analysis of lipid levels in mutant epidermis demonstrated profound defects in lipid homeostasis, illustrating for the first time the extent to which Abca12 plays a pivotal role in maintaining lipid balance in the skin. To further investigate the scope of Abca12's activity, we have utilised cells from the mutant mouse to ascribe direct transport functions to the protein and, in doing so, we demonstrate activities independent of its role in lamellar body function. These cells have severely impaired lipid efflux leading to intracellular accumulation of neutral lipids. Furthermore, we identify Abca12 as a mediator of Abca1-regulated cellular cholesterol efflux, a finding that may have significant implications for other diseases of lipid metabolism and homeostasis, including atherosclerosis.