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Dengue virus (DENV) causes the major arboviral disease of the tropics, characterized in its severe forms by signs of hemorrhage and plasma leakage. DENV encodes a nonstructural glycoprotein, NS1, that associates with intracellular membranes and the cell surface. NS1 is eventually secreted as a soluble hexamer from DENV-infected cells and circulates in the bloodstream of infected patients. Extracellular NS1 has been shown to modulate the complement system and to enhance DENV infection, yet its structure and function remain essentially unknown. By combining cryoelectron microscopy analysis with a characterization of NS1 amphipathic properties, we show that the secreted NS1 hexamer forms a lipoprotein particle with an open-barrel protein shell and a prominent central channel rich in lipids. Biochemical and NMR analyses of the NS1 lipid cargo reveal the presence of triglycerides, bound at an equimolar ratio to the NS1 protomer, as well as cholesteryl esters and phospholipids, a composition evocative of the plasma lipoproteins involved in vascular homeostasis. This study suggests that DENV NS1, by mimicking or hijacking lipid metabolic pathways, contributes to endothelium dysfunction, a key feature of severe dengue disease.

We recently demonstrated that daily whole egg consumption during moderate carbohydrate restriction leads to greater increases in plasma HDL-cholesterol (HDL-C) and improvements in HDL profiles in metabolic syndrome (MetS) when compared to intake of a yolk-free egg substitute. We further investigated the effects of this intervention on HDL composition and function, hypothesizing that the phospholipid species present in egg yolk modulate HDL lipid composition to increase the cholesterol-accepting capacity of subject serum. Men and women classified with MetS were randomly assigned to consume either three whole eggs (EGG, n  = 20) per day or the equivalent amount of egg substitute (SUB, n  = 17) throughout a 12-week moderate carbohydrate-restricted (25–30 % of energy) diet. Relative to other HDL lipids, HDL-cholesteryl ester content increased in all subjects, with greater increases in the SUB group. Further, HDL-triacylglycerol content was reduced in EGG group subjects with normal baseline plasma HDL-C, resulting in increases in HDL-CE/TAG ratios in both groups. Phospholipid analysis by mass spectrometry revealed that HDL became enriched in phosphatidylethanolamine in the EGG group, and that EGG group HDL better reflected sphingomyelin species present in the whole egg product at week 12 compared to baseline. Further, macrophage cholesterol efflux to EGG subject serum increased from baseline to week 12, whereas no changes were observed in the SUB group. Together, these findings suggest that daily egg consumption promotes favorable shifts in HDL lipid composition and function beyond increasing plasma HDL-C in MetS.

Background Obesity is associated with an atherogenic lipid profile characterized by a predominance of small LDL and HDL particles. Weight loss, by dietary restriction or exercise, increases LDL particle size. Whether these interventions can augment HDL size in conjunction with LDL size remains unknown. Objective This study compared the effects of alternate day fasting (ADF), calorie restriction (CR), and endurance exercise on LDL and HDL particle size in overweight and obese subjects. Methods In a 12-week parallel-arm trial, adult subjects (n = 60) were randomized to 1 of 4 groups: 1) ADF (75% energy restriction for 24-h alternated with ad libitum feeding for 24-h), 2) CR (25% energy restriction every day), 3) exercise (moderate intensity training 3 x/week), or 4) control. Results Body weight was reduced ( P < 0.001) by ADF, CR, and exercise (5.2 ± 1.1%, 5.0 ± 1.4%, 5.1 ± 0.9%, respectively). Plasma LDL cholesterol decreased ( P < 0.05) with ADF (10 ± 4%) and CR (8 ± 4%), whereas HDL cholesterol increased ( P < 0.05) with exercise (16 ± 5%). Integrated LDL particle size was augmented ( P = 0.01) by ADF and CR. The proportion of small LDL particles decreased ( P = 0.04) with ADF only, and the proportion of large HDL particles increased ( P = 0.03) with exercise only. Conclusion These results indicate that dietary restriction increases LDL particle size, while endurance training augments HDL particle size, with minimal weight loss. None of these interventions concomitantly increased both LDL and HDL particle size, however.

Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype Rabea Asleh 1 , Shany Blum 1 , Shiri Kalet-Litman 1 , Jonia Alshiek 1 , Rachel Miller-Lotan 1 , Roy Asaf 1 , Wasseem Rock 2 , Michael Aviram 2 , Uzi Milman 3 4 , Chen Shapira 5 6 , Zaid Abassi 7 and Andrew P. Levy 1 1 Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2 Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel 3 Clinical Research Unit, Clalit Health Services, Haifa and Western Galilee, Israel 4 Department of Family Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 5 Clalit Health Services, Haifa and Western Galilee, Israel 6 Lady Davis Carmel Medical Center, Haifa, Israel 7 Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Corresponding author: Andrew P. Levy, alevy{at}tx.technion.ac.il Abstract OBJECTIVE— Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction. RESEARCH DESIGN AND METHODS— Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters. RESULTS— Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes. CONCLUSIONS— Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008. Clinical trial reg. no. NCT00314379, clinicaltrials.gov . Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 26, 2008. Received April 2, 2008. DIABETES

Human sleeping sickness in east Africa is caused by the parasite Trypanosoma brucei rhodesiense . The basis of this pathology is the resistance of these parasites to lysis by normal human serum (NHS) 1 , 2 . Resistance to NHS is conferred by a gene that encodes a truncated form of the variant surface glycoprotein termed serum resistance associated protein (SRA) 3 , 4 . We show that SRA is a lysosomal protein, and that the amino-terminal α-helix of SRA is responsible for resistance to NHS. This domain interacts strongly with a carboxy-terminal α-helix of the human-specific serum protein apolipoprotein L-I (apoL-I). Depleting NHS of apoL-I, by incubation with SRA or anti-apoL-I, led to the complete loss of trypanolytic activity. Addition of native or recombinant apoL-I either to apoL-I-depleted NHS or to fetal calf serum induced lysis of NHS-sensitive, but not NHS-resistant, trypanosomes. Confocal microscopy demonstrated that apoL-I is taken up through the endocytic pathway into the lysosome. We propose that apoL-I is the trypanosome lytic factor of NHS, and that SRA confers resistance to lysis by interaction with apoL-I in the lysosome.

In obese individuals, atherogenic dyslipidemia is a very common and important factor in the increased risk of cardiovascular disease. Adiposity-associated dyslipidemia is characterized by low high-density lipoprotein cholesterol (HDL-C) levels and an increase in triglyceride-rich lipoproteins. Several factors and mechanisms are involved in lowering HDL-C levels in the obese state and HDL quantity and quality is closely related to adiponectin levels and the bioactive lipid sphingosine-1-phosphate. Recent studies have shown that obesity profoundly alters HDL metabolism, resulting in altered HDL subclass distribution, composition, and function. Importantly, weight loss through gastric bypass surgery and Mediterranean diet, especially when enriched with virgin olive oil, is associated with increased HDL-C levels and significantly improved metrics of HDL function. A thorough understanding of the underlying mechanisms is crucial for a better understanding of the impact of obesity on lipoprotein metabolism and for the development of appropriate therapeutic approaches. The objective of this review article was to summarize the newly identified changes in the metabolism, composition, and function of HDL in obesity and to discuss possible pathophysiological consequences.

Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM⁺ HDL contained S1P, whereas ApoM⁻ HDL did not. Moreover, HDL in Apom⁻/⁻ mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM⁺ HDL induced S1P₁ receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM⁻ HDL did not. Importantly, lack of S1P in the HDL fraction of Apom⁻/⁻ mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P₁ receptor on endothelial cells, is a vasculoprotective constituent of HDL.

Diabetic dyslipoproteinemia is characterized by low HDL cholesterol and high triglycerides. We examined the association of lipoprotein particle size and concentration measured by nuclear magnetic resonance (NMR) spectroscopy with clinical type 2 diabetes. This was a prospective study of 26,836 initially healthy women followed for 13 years for incident type 2 diabetes (n = 1,687). Baseline lipids were measured directly and lipoprotein size and concentration by NMR. Cox regression models included nonlipid risk factors (age, race, smoking, exercise, education, menopause, blood pressure, BMI, family history, A1C, and C-reactive protein). NMR lipoproteins were also examined after further adjusting for standard lipids. Incident diabetes was significantly associated with baseline HDL cholesterol, triglycerides, and NMR-measured size and concentration of LDL, IDL, HDL, and VLDL particles. The associations of these particles differed substantially by size. Small LDL(NMR) and small HDL(NMR) were positively associated with diabetes (quintile 5 vs. 1 [adjusted hazard ratios and 95% CIs], 4.04 [3.21-5.09] and 1.84 [1.54-2.19], respectively). By contrast, large LDL(NMR) and large HDL(NMR) were inversely associated (quintile 1 vs. 5, 2.50 [2.12-2.95] and 4.51 [3.68-5.52], respectively). For VLDL(NMR), large particles imparted higher risk than small particles (quintile 5 vs. 1, 3.11 [2.35-4.11] and 1.31 [1.10-1.55], respectively). Lipoprotein particle size remained significant after adjusting for standard lipids and nonlipid factors. In this prospective study of women, NMR lipoprotein size and concentrations were associated with incident type 2 diabetes and remained significant after adjustment for established risk factors, including HDL cholesterol and triglycerides.

Chronic kidney disease (CKD) ultimately causes renal fibrosis and end-stage renal disease, thus seriously threatens human health. However, current medications for CKD and fibrosis are inefficient, which is often due to poor targeting capability to renal tubule. In this study, we discover that biomimetic high-density lipoprotein (bHDL) lipid nanoparticles possess excellent targeting ability to injured tubular epithelial cells by kidney injury molecule-1(KIM-1) mediated internalization. Thus, we co-load anti-inflammatory drug triptolide (TP) and anti-fibrotic drug nintedanib (BIBF) on bHDL nanoparticles to treat CKD. Based on the targeted delivery and mutual enhancement of the efficacy of co-delivered drugs, the bHDL-based system effectively reduces kidney injury and alleviates renal fibrosis in different CKD mouse models. The mechanistic study shows that BIBF and TP synergistically remodel the fibrotic niches by decreasing inflammatory cytokines, limiting immune cell infiltration and inhibiting the activation of myofibroblasts. The bHDL vehicle also possesses high manufacturability, good safety and adequately reduces the toxicity of TP. Thus, this system is promising for the treatment of CKD and bHDL has good potential for delivering agents to damaged renal tubular epithelial cells. Effectively delivering medications to the renal tubule to delay or halt chronic kidney disease progression remains a significant unmet clinical challenge. Here, authors introduce an innovative strategy for renal tubule targeting using biomimetic high-density lipoprotein (bHDL) nanoparticles.

This study shows that Trypanosoma brucei gambiense resists trypanolytic factors (TLFs) in a multifactorial manner, relying on a hydrophobic β-sheet of the TgsGP glycoprotein, which prevents APOL1 toxicity and induces membrane stiffening, as well as a reduction in sensitivity to APOL1 requiring cysteine protease activity and TLF-1 receptor inactivation owing to a single amino acid substitution. Trypanosomal resistance to APOL1 Humans are normally protected against trypanosomal pathogens by the serum antiparasitic molecule apolipoprotein LI (APOL1). But two Trypanosoma brucei subspecies — rhodesiense and gambiense — can resist APOL1 and it is these that cause almost all human sleeping sickness cases. This paper describes the mechanism by which T. b. gambiense resists APOL1. Three complementary processes are involved: reduced APOL1 uptake, increased APOL1 degradation and APOL1 target membrane modification by a specific resistance factor. This resistance can be bypassed under some conditions, opening up new possibilities for intervention against the parasite. The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases 1 . T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei , the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1) 2 , 3 , 4 . Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5 ), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4 , 5 ). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes 2 , 6 , 7 . Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense -specific glycoprotein (TgsGP) 8 , which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa 9 .