In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality also appears to be very important for atheroprotection. Analysis of various clinical paradigms suggests that the lipid and apolipoprotein composition of HDL defines its size, shape, and functions and may determine its beneficial effects on human health. Previously, we reported that like apolipoprotein A-I (Apoa1), apolipoprotein E (Apoe) is also capable of promoting the de novo biogenesis of HDL with the participation of ATP binding cassette A lipid transporter member 1 (Abca1) and plasma enzyme lecithin:cholesterol acyltransferase (Lcat), in a manner independent of a functional Apoa1. Here, we performed a comparative analysis of the functions of these HDL subpopulations. Specifically, Apoe and Apoa1 double-deficient (Apoe(-/-) × Apoa1(-/-)) mice were infected with APOA1- or APOE3-expressing adenoviruses, and APOA1-containing HDL (APOA1-HDL) and APOE3-containing HDL (APOE3-HDL), respectively, were isolated and analyzed by biochemical and physicochemical methods. Western blot and lipidomic analyses indicated significant differences in the apolipoprotein and lipid composition of the two HDL species. Moreover APOE3-HDL presented a markedly reduced antioxidant potential and Abcg1-mediated cholesterol efflux capacity. Surprisingly, APOE3-HDL but not APOA1-HDL attenuated LPS-induced production of TNFα in RAW264.7 cells, suggesting that the anti-inflammatory effects of APOA1 are dependent on APOE expression. Taken together, our data indicate that APOA1 and APOE3 recruit different apolipoproteins and lipids on the HDL particle, leading to structurally and functionally distinct HDL subpopulations. The distinct role of these two apolipoproteins in the modulation of HDL functionality may pave the way toward the development of novel pharmaceuticals that aim to improve HDL functionality.

Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1 − / − mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1 − / − femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1 − / − mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1 − / − mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1 − / − mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1 − / − animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1 − / − phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.Laboratory Investigation (2016) 96, 763-772; doi:10.1038/labinvest.2016 published online 18 April 2016 Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, resulting in bone fragility and fracture susceptibility. 1,2 It is a major public health problem worldwide; indeed, in the United States, more than 44 million people have osteoporosis or low bone mass. 3 The pathogenesis of osteoporosis is multifactorial. Age, sex, body size, metabolic factors, and genetic susceptibility are contributory factors. Interestingly, several studies have shown that there are strong links between bone, fat metabolism, and systemic energy metabolism, and that perturbations in lipid regulatory pathways may trigger both local and systemic phenomena that ultimately affect osteoblast and/or osteoclast function, resulting...

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Our findings suggest that perturbations in HDL metabolism predispose to OA following chronic insult with WTD and raise the challenging possibility that HDL has a causative relation to OA in patients with metabolic syndrome.

Epidemiological and clinical studies have over the years established that dyslipidemia constitutes the main risk factor for atherosclerosis. The inverse correlation between HDL cholesterol (HDL-C) levels and coronary heart disease morbidity and mortality identified HDL-C as an alternative pharmacological target to LDL-C and a potential anti-atherosclerosis marker. However, more recent data reinforced the principle of 'HDL quality' in atherosclerosis that refers to the functionality of HDL particle, as defined by its protein and lipid content, rather than HDL-C levels in plasma. Since HDL functionality depends on the genes and proteins of the HDL metabolic pathway, its apoprotein composition may serve as a surrogate marker of atheroprotection. In this manuscript we review the atheroprotective properties of HDL in relation to the proteins of HDL metabolic pathway and discuss what HDL-associated genes and proteins may reveal about HDL functionality in the assessment of coronary risk.

Emerging evidence strongly supports that changes in the HDL metabolic pathway, which result in changes in HDL proteome and function, appear to have a causative impact on a number of metabolic disorders. Here, we provide a critical review of the most recent and novel findings correlating HDL properties and functionality with various pathophysiological processes and disease states, such as obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, inflammation and sepsis, bone and obstructive pulmonary diseases, and brain disorders.

HDL has important immunomodulatory properties, including the attenuation of lipopolysaccharide (LPS)-induced inflammatory response. As lecithin-cholesterol acyltransferase (LCAT) is a critical enzyme in the maturation of HDL we investigated whether LCAT-deficient (Lcat(-/-)) mice present an increased LPS-induced inflammatory response. LPS (100μg/kg body weight)-induced cytokine response in Lcat(-/-) mice was markedly enhanced and prolonged compared to wild-type mice. Importantly, reintroducing LCAT expression using adenovirus-mediated gene transfer reverted their phenotype to that of wild-type mice. Ex vivo stimulation of whole blood with LPS (1-100ng/mL) showed a similar enhanced pro-inflammatory phenotype. Further characterization in RAW 264.7 macrophages in vitro showed that serum and HDL, but not chylomicrons, VLDL or the lipid-free protein fraction of Lcat(-/-) mice, had a reduced capacity to attenuate the LPS-induced TNFα response. Analysis of apolipoprotein composition revealed that LCAT-deficient HDL lacks significant amounts of ApoA-I and ApoA-II and is primarily composed of ApoE, while HDL from Apoa1(-/-) mice is highly enriched in ApoE and ApoA-II. ApoA-I-deficiency did not affect the capacity of HDL to neutralize LPS, though Apoa1(-/-) mice showed a pronounced LPS-induced cytokine response. Additional immunophenotyping showed that Lcat(-/-) , but not Apoa1(-/-) mice, have markedly increased circulating monocyte numbers as a result of increased Cd11b(+)Ly6C(med) monocytes, whereas 'pro-inflammatory' Cd11b(+)Ly6C(hi) monocytes were reduced. In line with this observation, peritoneal macrophages of Lcat(-/-) mice showed a markedly dampened LPS-induced TNFα response. We conclude that LCAT-deficiency increases LPS-induced inflammation in mice due to reduced LPS-neutralizing capacity of immature discoidal HDL and increased monocyte number.

Apolipoprotein E is a polymorphic glycoprotein in humans with a molecular mass of 34.5 kDa. It is a component of chylomicron remnants, very low density lipoprotein, low density lipoprotein and high density lipoprotein, and is primarily responsible for maintaining plasma lipid homeostasis. In addition to these well‐documented functions, recent studies in experimental mouse models, as well as population studies, show that apolipoprotein E also plays an important role in the development of obesity and insulin resistance. It is widely accepted that disruption in homeostasis between food intake and energy expenditure, and the subsequent deposition of excess fatty acids into fat cells in the form of triglycerides, leads to the development of obesity. Despite the pivotal role of obesity and dyslipidemia in the development of the metabolic syndrome and heart disease, the functional interactions between adipose tissue and components of the lipoprotein transport system have not yet been investigated thoroughly. In this minireview, we focus on the current literature pertinent to the involvement of apolipoprotein E in the development of pathologies associated with the metabolic syndrome.