The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism.

Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.

Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits.

OBJECTIVE: Scavenger receptor-class B type I (SR-BI), the receptor for HDL-cholesterol, plays a key role in HDL metabolism, whole body cholesterol homeostasis, and reverse cholesterol transport. We investigated the in vivo impact of hepatic SR-BI inhibition on lipoprotein metabolism and the development of atherosclerosis employing RNA interference. METHODS: Small hairpin RNA plasmid specific for rabbit SR-BI was complexed with galactosylated poly-l-lysine, allowing an organ-selective, receptor-mediated gene transfer. Rabbits were fed a cholesterol-rich diet, and were injected with plasmid-complexes once a week. RESULTS: After 2 weeks of treatment hepatic SR-BI mRNA levels were reduced by 80% accompanied by reduced SR-BI protein levels and a modulation of the lipoprotein profile. Rabbits treated with SR-BI-specific plasmid-complexes displayed higher cholesteryl ester transfer from HDL to apoB-containing lipoproteins, lower HDL-cholesterol, and higher VLDL-cholesterol levels, when compared to controls. In a long-term study, this gene therapeutic intervention led to a similar modulation of the lipoprotein profile, to lower total cholesterol levels, and most importantly to a 50% reduction of the relative atherosclerotic lesion area. CONCLUSION: Our results are another indication that the role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits--a CETP-expressing animal model displaying a manlike lipoprotein profile may be different from the one found in rodents.

Leoligin, the major lignan from Edelweiss, activates cholesteryl ester transfer protein.

OBJECTIVE: Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of high-density lipoprotein particles. Therefore, we searched for new drugs that bind to CETP and modulate its activity. METHODS: A preliminary pharmacophore-based parallel screening approach indicated that leoligin, a major lignan of Edelweiss (Leontopodium alpinum Cass.), might bind to CETP. Therefore we incubated leoligin ex vivo at different concentrations with human (n=20) and rabbit plasma (n=3), and quantified the CETP activity by fluorimeter. Probucol served as positive control. Furthermore, we dosed CETP transgenic mice with leoligin and vehicle control by oral gavage for 7 days and measured subsequently the in vivo modulation of CETP activity (n=5 for each treatment group). RESULTS: In vitro, leoligin significantly activated CETP in human plasma at 100 pM (p=0.023) and 1 nM (p=0.042), respectively, whereas leoligin concentrations of 1 mM inhibited CETP activity (p=0.012). The observed CETP activation was not species specific, as it was similar in magnitude for rabbit CETP. In vivo, there was also a higher CETP activity after oral dosage of CETP transgenic mice with leoligin (p=0.015). There was no short-term toxicity apparent in mice treated with leoligin. CONCLUSION: CETP agonism by leoligin appears to be safe and effective, and may prove to be a useful modality to alter high-density lipoprotein metabolism.

Postprandial triglyceride-rich lipoproteins induce hepatic insulin resistance in HepG2 cells independently of their receptor-mediated cellular uptake.

Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance with the molecular basis of this association being not well understood. Here we studied the effect of hepatic triglyceride accumulation induced by postprandial triglyceride-rich lipoproteins (TGRL) on hepatic insulin sensitivity in HepG2 cells. Incubation of HepG2 cells with purified TGRL particles induced hepatocellular triglyceride accumulation paralleled by diminished insulin-stimulated glycogen content and glycogen synthase activity. Accordingly, insulin-induced inhibition of glycogen synthase phosphorylation as well as insulin-induced GSK-3 and AKT phosphorylation were reduced by TGRL. The effects of TGRL were dependent on the presence of apolipoproteins and more pronounced for denser TGRL. Moreover, TGRL effects required the presence of heparan sulfate-proteoglycans on the cell membrane and lipase activity but were independent of the cellular uptake of TGRL particles by receptors of the LDL receptor family. We suggest postprandial lipemia to be an important factor in the pathogenesis of NAFLD.

A murine model of phosphate nephropathy.

We established a murine model of phosphate nephropathy with secondary hyperparathyroidism. db/db mice, which develop obesity and type 2 diabetes mellitus, were uninephrectomized at the age of 6 weeks and were fed either standard chow or a phosphorus-rich diet during the next 8 weeks. Thereafter, renal cryosections showed abundant tubular casts with a strong histochemical von Kossa reaction in all db/db mice on the phosphorus-rich diet but none in the controls. X-ray diffraction and Raman spectroscopy proved that these tubular casts consist mostly of hydroxyapatite Ca5(PO4)3(OH). These intraluminal precipitations were located in distal tubuli and collecting ducts and were associated with degenerative tubular changes and peritubular infiltration of T cells and macrophages. In line, kidneys of db/db mice on the phosphorus-rich diet displayed significantly increased mRNA expression of the T(H)1 cytokines interferon γ, IL-6, and tumor necrosis factor α. In addition, mice developed signs of secondary hyperparathyroidism as shown by elevated serum phosphate, decreased serum calcium, and increased parathyroid hormone, osteopontin, and fibroblast growth factor 23 levels. db/db mice on the phosphorus-rich diet also presented with significantly lower body weight, lower homeostasis model assessment of insulin resistance index, and hypertrophic cardiomyopathy. Thus, we provide a murine model of phosphate nephropathy and secondary hyperparathyroidism, which can be used for future pharmacologic and pathophysiologic studies to analyze the effect of hyperphosphatemia on renal, metabolic, and cardiovascular phenotypes.

Cholesteryl ester transfer protein and hepatic lipase gene polymorphisms: effects on hepatic mRNA levels, plasma lipids and carotid atherosclerosis.

OBJECTIVE: HDL modifying effects of cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) depend in part on each other. We studied associations of CETP-Taq1B and -514C>T-LIPC polymorphisms with hepatic mRNA levels, and their combined effects on plasma lipids and carotid atherosclerosis. METHODS: We genotyped the CETP-Taq1B and the -514C>T-LIPC polymorphisms in 67 obese women in whom hepatic CETP and LIPC transcript levels were determined as well as in 1549 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR). Carotid atherosclerosis was assessed by intima-media thickness and extent of plaques (B-score) of the carotid arteries. RESULTS: In obese women, CETP-Taq1B and -514C>T-LIPC variant alleles were associated with reduced hepatic levels of CETP and LIPC mRNA, respectively. The CETP and LIPC polymorphisms accounted for 12.9 and 14.4% of the variability in respective transcripts. In the SAPHIR population, CETP-Taq1B showed independent effects on LDL diameter, HDL and LDL cholesterol, apolipoproteins AI and B and cholesterol/HDL cholesterol, while -514C>T-LIPC revealed independent effects on HDL cholesterol and apolipoprotein AI. The two polymorphisms displayed interactions at the level of HDL cholesterol. Compared to subjects carrying wild-type alleles at both loci, subjects homozygous for the CETP wild-type allele, but heterozygous for the LIPC polymorphism and subjects heterozygous for the CETP polymorphism, but homozygous for the LIPC wild-type allele showed an increased risk of carotid atherosclerosis (both P<0.05). CONCLUSIONS: CETP and LIPC polymorphisms influence the respective hepatic transcript levels, demonstrate interactions on HDL cholesterol and suggest that imbalances between CETP and LIPC activities may modulate the risk of carotid atherosclerosis.

Effect of weight loss on serum pigment epithelium-derived factor levels.

BACKGROUND: Cumulating evidence suggests that the broadly acting neurotrophic pigment epithelium-derived factor is associated with visceral adiposity, the metabolic syndrome, diabetes and exerts beneficial effects on atherosclerosis. To further elucidate the relationship between pigment epithelium-derived factor and metabolic perturbations characteristic of obesity, we examined the effect of pronounced weight loss on serum levels of pigment epithelium-derived factor. MATERIALS AND METHODS: Thirty-six severely obese adults were examined before and 18 months after bariatric surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters by standard methods, pro-inflammatory biomarkers and serum pigment epithelium-derived factor levels by enzyme-linked immunosorbent assay. RESULTS: Bariatric surgery resulted in a mean body mass index (BMI) reduction of 9·0 ± 5·0 kg m(-2) and concomitant improvements in glucose homoeostasis and lipid profile. Pigment epithelium-derived factor serum levels decreased from a median 11·0 µg mL(-1) (interquartile range: 3·8) to 9·2 µg mL(-1) (interquartile range: 4·5) (P < 0·0001). In univariate analysis, relative change in pigment epithelium-derived factor levels was significantly associated with change in weight, BMI, fat mass, visceral fat diameter, insulin, homoeostasis model for insulin resistance, triglyceride and leptin levels (all r > 0·370, P < 0·05). No associations were observed for C-reactive protein, interleukin-6 or tumour necrosis factor alpha. After adjustment for age, sex and smoking status, associations remained significant. CONCLUSIONS: The beneficial effects of bariatric surgery-induced pronounced weight loss on glucose homoeostasis may partially be attributable to visceral adipose tissue reduction and concomitantly decreasing pigment epithelium-derived factor concentrations.

[LDL-cholesterol in secondary prevention: goal-attainment in patients on lipid-lowering drugs in private practice and in hospitals in Austria (ZIEL)]. / LDL-Cholesterin in der Sekundärprävention: Zielwert-Erreichung unter Lipidsenkern in Praxis und Spital in Österreich (ZIEL).

BACKGROUND: A hospital-based screening project (HSP) in Austria found 47% of high-risk patients (LDL-C < 100 mg/dl) and 24% of very high-risk patients (LDL-C < 70 mg/dl) at goal. Separate data for the sexes were not reported. We analyze whether LDL-C goal attainment in patients with manifest atherosclerosis and/or diabetes on stable lipid-lowering treatment differs between private practice and hospital and between men and women. PATIENTS AND METHODS: From September to November 2007, 49 Austrian centers (36 private practice, 13 hospitals) documented vascular morbidity, lipid levels, and lipid lowering treatment in patients with high risk (atherosclerosis or diabetes, n = 978) and very high risk (coronary heart disease and diabetes or acute coronary syndrome, n = 322). RESULTS: 75% and 25% of the 1300 patients were high and very high risk, respectively. LDL-C goals of < 100 and < 70 mg/dl, respectively, were attained by 45.4% and 26.4% of patients (p < 0.001). A similar percentage of patients with very high risk was found in men and women (26.4% vs. 22.9%, NS) and goal attainment was not influenced by sex (high risk: 47.2% (m) vs. 43.8% (w), NS and very high risk: 29.1% (m) vs. 22.4% (w), NS). In patients with high risk, 41.6% treated in private practice vs. 57.9% treated in the hospital were at goal (p < 0.001). In patients with very high risk, 15.9% treated in private practice vs. 45.2% treated in the hospital were at goal (p < 0.001). Lower goal-attainment in private practice occurred despite significantly more intensive lipid intervention and probably reflects higher baseline LDL-C. LDL-C > 100 mg/dl leads to a more aggressive lipid lowering in approx. 70% of patients, irrespective of whether they are treated in private practice or in the hospital. LDL-C between 70 and 100 mg/dl, however, leads to a more aggressive lipid lowering in < 5% of patients, irrespective of whether they are high or very high risk. CONCLUSION: As observed in EUROASPIRE III for other European countries, there is substantial potential for improvement in lipid control in Austrian cardiovascular high-risk patients, irrespective of whether they are treated in private practice or in the hospital.

Differential effects of NO inhibition in renal epithelial and endothelial cells in mono-culture vs. co-culture conditions.

Nitric oxide (NO) plays a critical role in the regulation of renal hemodynamics and tubular function after post-ischemic damage or sepsis. Diminished NO bioavailability contributes to endothelial dysfunction and may be caused by reduced NO synthesis due to substrate or co-factor deficiency. The aim of this study was to investigate the effects of NOS inhibition and NO depletion in a renal endo-epithelial bilayer model compared to monolayers of proximal tubular epithelial (HK-2) cells and endothelial cells of venous origin (EA.hy 926) with respect to cellular integrity, apoptosis and cytokine release. Two different NOS inhibitors have been used: an arginine-based-inhibitor, L-N(G)monomethyl-arginine (L-NMMA) and a cofactor-based-inhibitor, H4-amino-biopterin (4-ABH(4)) showing iNOS selectivity. We found significantly higher basal NO production by epithelial than by endothelial monolayers, which was significantly reduced by both NOS-inhibitors with a stronger effect demonstrated by 4-ABH(4). Furthermore we detected significant basal iNOS protein expression in unstimulated HK-2 cells. NOS inhibition by 4-ABH(4) was associated with increased LDH release, apoptosis and reduced IL-6 production in epithelial but not in endothelial monolayers. These effects on epithelial cells were abolished under co-culture conditions. In contrast, endothelial cells showed higher IL-6 and IL-8 release under co-culture conditions than in monolayers, with IL-8 production being largely suppressed by L-NMMA but not by 4-ABH(4). In conclusion, inhibition of basal NO production in epithelial monolayers shows detrimental effects on cell integrity and viability. Under co-culture conditions interrelation between epithelial and endothelial cells appears to counteract these potentially harmful effects of epithelial NOS inhibition.

The neuropeptide catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism.

RATIONALE: The neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone. OBJECTIVE: Catestatin shares several functions with angiogenic factors. We therefore reasoned that catestatin induces growth of new blood vessels. METHODS AND RESULTS: Catestatin induced migration, proliferation, and antiapoptosis in endothelial cells and exerted capillary tube formation in vitro in a Matrigel assay, and such effects were mediated via G protein, mitogen-activated protein kinase, and Akt. Catestatin-induced endothelial cell functions are further mediated by basic fibroblast growth factor, as shown by blockade of effects by a neutralizing fibroblast growth factor antibody. Furthermore, catestatin released basic fibroblast growth factor from endothelial cells and stimulated fibroblast growth factor signaling. In addition to its function on endothelial cells, catestatin also exerted effects on endothelial progenitor cells and vascular smooth muscle cells. In vivo, catestatin induced angiogenesis in the mouse cornea neovascularization assay and increased blood perfusion and number of capillaries in the hindlimb ischemia model. In addition to angiogenesis, catestatin increased density of arterioles/arteries and incorporation of endothelial progenitor cells in the hindlimb ischemia model, indicating induction of arteriogenesis and postnatal vasculogenesis. CONCLUSION: We conclude that catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism.

Cholesteryl ester transfer protein in patients with coronary heart disease.

BACKGROUND: The impact of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is a matter for ongoing debate. In this study, we analyse associations of CETP with cardiovascular endpoints in a cohort of patients with stable coronary artery disease (CAD). DESIGN: KAROLA is a prospective observational study of patients with CAD and a median follow-up of 8 years (n = 1132). CETP levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Cholesteryl ester transfer protein levels were lower in men (P = 0.0016), positively correlated to low-density lipoprotein cholesterol, and inversely correlated to triglyceride levels (P < 0.0001 and P = 0.011 respectively). There was no significant difference in mortality between patients in different CETP quartiles; the hazard ratio of lowest vs. highest quartile was 1.33 (95% confidence interval (CI): 0.77-2.30) for mortality and 1.24 (95% CI: 0.75-2.03) for secondary events. In post hoc analyses, comparing nondiabetic subjects with CETP below vs. above median, the adjusted hazard ratio for death in patients with low CETP levels was 1.84 (95% CI: 1.10-3.09). CONCLUSION: Although statistically significant associations were found only in post hoc analyses, the effect sizes in this study were in line with previous findings in the Framingham and LURIC population. In combination, the emerging evidence challenges the concept of pharmacological CETP inhibition.

Influence of significant weight loss on serum matrix metalloproteinase (MMP)-7 levels.

BACKGROUND: Matrix metalloproteinases (MMPs) and their specific inhibitors (tissue inhibitor of metalloproteinases [TIMPs]), are involved in adipogenesis, angiogenesis and remodeling of extracellular matrix. MMPs and TIMPs have been shown to be associated with various diseases such as neurological disorders, malignancies and cardiovascular disease. MMPs and TIMPs are thought to play a major role in extensive reorganization of the adipose tissue in obesity. METHODS AND MATERIALS: To test whether significant weight loss alters circulating MMPs and TIMPs, 18 morbidly obese women, who underwent bariatric surgery for weight loss, were investigated before and one year after surgery in a prospective design study. Body composition, glucose and lipid metabolism parameters were determined in all study subjects before and after weight loss. Circulating MMP-2, -3, -7 and TIMP-1, -2 and -4 serum levels were measured using commercially available, enzyme-linked immunoassays. RESULTS: Pronounced weight loss was accompanied by improvements in glucose homeostasis and lipid parameters. In the mean time MMP-2 and MMP-3, as well as TIMP-1, -2 and TIMP-4 concentrations were not affected by significant weight loss, and circulating MMP-7 increased significantly after bariatric surgery, although without reaching the standard levels as determined in 18, lean, healthy women. CONCLUSION: Our data indicate that reduced MMP-7 levels in obesity might be restored by significant weight loss, suggesting that the reorganization of adipose tissue in obesity might be partially reversible by weight reduction. We hypothesize that increased circulating MMP-7 might indicate enhanced adipocyte differentiation in subjects who had undergone bariatric surgery.

Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study.

BACKGROUND: The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still open to debate. In the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, inhibition of CETP in patients with high cardiovascular risk was associated with increased high-density lipoprotein levels but increased risk of cardiovascular morbidity and mortality. In this report, we present a prospective observational study of patients referred to coronary angiography in which CETP was examined in relation to morbidity and mortality. METHODS AND RESULTS: CETP concentration was determined in 3256 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 7.75 years. Primary and secondary end points were cardiovascular and all-cause mortality, respectively. CETP levels were higher in women and lower in smokers, in diabetic patients, and in patients with unstable coronary artery disease, respectively. In addition, CETP levels were correlated negatively with high-sensitivity C-reactive protein and interleukin-6. After adjustment for age, sex, medication, coronary artery disease status, cardiovascular risk factors, and diabetes mellitus, the hazard ratio for death in the lowest CETP quartile was 1.33 (1.07 to 1.65; P=0.011) compared with patients in the highest CETP quartile. Corresponding hazard ratios for death in the second and third CETP quartiles were 1.17 (0.92 to 1.48; P=0.19) and 1.10 (0.86 to 1.39; P=0.46), respectively. CONCLUSIONS: We interpret our data to suggest that low endogenous CETP plasma levels per se are associated with increased cardiovascular and all-cause mortality, challenging the rationale of pharmacological CETP inhibition.

The liver-selective thyromimetic T-0681 influences reverse cholesterol transport and atherosclerosis development in mice.

BACKGROUND: Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls. CONCLUSIONS/SIGNIFICANCE: The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans.

Atorvastatin attenuates murine anti-glomerular basement membrane glomerulonephritis.

Statins mediate many of their protective effects by lowering lipids as well as by modulating inflammation. Here, we studied their potential immunomodulatory role in renal inflammation using an autoimmune mouse model of anti-glomerular basement membrane glomerulonephritis. Oral treatment with Atorvastatin dramatically reduced albuminuria and histological changes in the kidneys as compared to vehicle-treated control animals. There was a significant decrease in the Th1 and Th17 response in the regional lymph nodes draining the kidneys. This systemic effect was accompanied by decreased infiltration of the kidneys with inflammatory CD4(+) T and Th17 cells, macrophages, and neutrophils in statin-treated mice. Regulatory T cells were not altered in their number, FoxP3 expression, or suppressive capacity, but their interleukin-10 production was significantly increased by statin treatment. Hence, Atorvastatin systemically and locally decreased the Th1 and Th17 response, thereby protecting the mice against anti-glomerular basement membrane glomerulonephritis. Whether statins can be used to treat human autoimmune renal diseases will require more direct studies.

Effects of weight loss on lipid transfer proteins in morbidly obese women.

Obesity is associated with lipid abnormalities leading to an increased morbidity and mortality from atherosclerotic disease. Lipid transfer proteins such as Cholesteryl Ester Transfer Protein (CETP) and Phospholipid Transfer Protein (PLTP), and lipases such as lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in the pathogenesis of the obesity associated proatherogenic dyslipidemia. Nineteen severely obese female subjects undergoing laparosopic gastric banding participated in this prospective study. Subjects were examined with respect to body composition, lipid profile, CETP, PLTP, LPL and HL before and 1 year after surgical treatment. Mean weight loss was 22.2 kg, mainly due to losses in the fat depots. Triglycerides decreased and HDL(2)-C increased significantly. In respect to transfer proteins mean CETP mass decreased from 1.82 to 1.71 microg mL(-1) (P = 0.043) and mean PLTP activity was reduced from 7.15 to 6.12 micromol mL(-1) h(-1) (P = 0.002), in parallel. In addition, both mean LPL activity and mean HL activity tended to decrease from 297 to 248 nmol mL(-1) h(-1) for LPL (P = 0.139) and from 371 to 319 nmol mL(-1) h(-1) for HL (P = 0.170), respectively. We conclude that weight loss induced by bariatric surgery is associated with the amelioration of the obesity-associated dyslipidemic state. This improvement may be attributable to decreased mass and action of the adipocyte tissue derived lipid transfer proteins CETP and PLTP.

Gene therapy with the angiogenic cytokine secretoneurin induces therapeutic angiogenesis by a nitric oxide-dependent mechanism.

RATIONALE: The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells. OBJECTIVE: We sought to investigate the effects of secretoneurin on therapeutic angiogenesis. METHODS AND RESULTS: We generated a secretoneurin gene therapy vector. In the mouse hindlimb ischemia model secretoneurin gene therapy by intramuscular plasmid injection significantly increased secretoneurin content of injected muscles, improved functional parameters, reduced tissue necrosis, and restored blood perfusion. Increased muscular density of capillaries and arterioles/arteries demonstrates the capability of secretoneurin gene therapy to induce therapeutic angiogenesis and arteriogenesis. Furthermore, recruitment of endothelial progenitor cells was enhanced by secretoneurin gene therapy consistent with induction of postnatal vasculogenesis. Additionally, secretoneurin was able to activate nitric oxide synthase in endothelial cells and inhibition of nitric oxide inhibited secretoneurin-induced effects on chemotaxis and capillary tube formation in vitro. In vivo, secretoneurin induced nitric oxide production and inhibition of nitric oxide attenuated secretoneurin-induced effects on blood perfusion, angiogenesis, arteriogenesis, and vasculogenesis. Secretoneurin also induced upregulation of basic fibroblast growth factor and platelet-derived growth factor-B in endothelial cells. CONCLUSIONS: In summary, our data indicate that gene therapy with secretoneurin induces therapeutic angiogenesis, arteriogenesis, and vasculogenesis in the hindlimb ischemia model by a nitric oxide-dependent mechanism.

The resurgence of thyromimetics as lipid-modifying agents.

The aggressive reduction of LDL-cholesterol levels by treatment with statins is a key component of preventive cardiovascular care; however, additional therapies to prevent atherosclerosis and the associated clinical sequelae are still needed. Thyromimetic compounds selective for the liver or for the thyroid hormone receptor isoform beta1 constitute a novel approach for the treatment of dyslipidemia. In preclinical studies, selective thyromimetics significantly reduced plasma cholesterol levels and provided protection from atherosclerosis by upregulating the hepatic LDL receptor and promoting reverse cholesterol transport. Importantly, data from ongoing clinical trials have provided the first evidence that selective thyromimetics may also reduce the levels of plasma cholesterol in humans.

Effect of bariatric surgery on both functional and structural measures of premature atherosclerosis.

AIMS: To bridge the beneficial metabolic effects of pronounced weight loss on one side and the data on morbidity and mortality on the other side, we investigated the impact of profound weight loss on structural and functional markers of early atherosclerosis. METHODS AND RESULTS: Thirty-seven obese adults were examined before and 18 months after bariatric surgery. Carotid intima-media thickness (CIMT), brachial flow-mediated dilation (FMD), nitroglycerine-mediated dilation, and abdominal fat distribution were assessed by high-resolution ultrasound. Surgery resulted in a body mass index decrease of 9.1 +/- 4.9 kg/m(2) with concomitant improvements in glucose and lipid metabolism. Carotid intima-media thickness diminished from 0.56 +/- 0.09 to 0.53 +/- 0.08 mm (n = 37; P = 0.004). Flow-mediated dilation improved from 5.81 +/- 3.25 to 9.01 +/- 2.93% (n = 25; P < 0.001). Both CIMT and FMD were associated with intra-abdominal fat diameter. CONCLUSION: The present results demonstrate that bariatric surgery-induced diminution of visceral fat improves both functional and structural markers of early atherosclerosis, providing a link between the weight loss-associated improvements of traditional and non-traditional risk factors and the reduced long-term morbidity and mortality after bariatric surgery.

Adipocyte fatty acid binding protein during refeeding of female patients with anorexia nervosa.

BACKGROUND: Adipocyte fatty acid binding protein (A-FABP) has been suggested to play an important role in fat metabolism linking obesity and the metabolic syndrome. Increasing A-FABP plasma levels were observed during greatest weight loss after bariatric surgery suggesting that A-FABP may indicate changes in fat mass in dynamic situations. AIM OF THE STUDY: As there are no data on weight gain, we investigated the effect of refeeding anorexic patients on body composition and A-FABP plasma levels. METHODS: Parameters of glucose and lipid metabolism as well as plasma levels of leptin and A-FABP were prospectively assessed in 16 female patients with anorexia nervosa during inpatient weight restoration. Body composition was determined by multifrequency body impedance analysis. RESULTS: After 28 days, fat mass increased from 4.4 +/- 2.5 kg at baseline to 5.5 +/- 2.2 kg (P < 0.01), constituting 40% of total weight gain. Conversely, A-FABP concentrations decreased from 32.56 +/- 35.59 ng/ml at baseline to 21.27 +/- 13.68 ng/ml (P < 0.05), which corresponds to a significant decrease in the proportion of A-FABP per kilogram fat mass from 7.86 +/- 5.23 to 4.09 +/- 2.12 ng/ml/kg (P