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BACKGROUND. Cellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay. METHODS. We developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on wholeplasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels. RESULTS. Receiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001). CONCLUSION. HDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery. TRIAL REGISTRATION. ClinicalTrials.gov NCT01621594. FUNDING. NHLBI Intramural Research Program, NIH (HL006095-06)., Introduction Coronary artery disease (CAD) risk assessment is a critical step for determining the need for lipid-lowering therapy (1). HDL-cholesterol (HDL-C) and total cholesterol are the 2 lipid tests currently [...]

Liver cirrhosis is a catabolic disease associated with a high incidence of insulin resistance and diabetes mellitus. Pre-B cell colony-enhancing factor/nicotinamide phosphoribosyltransferase/visfatin has been characterized as a novel adipokine with a potential role in glucose metabolism and nicotinamide dinucleotide (NAD) generation. We studied plasma levels and metabolic relevance of visfatin in 19 patients with cirrhosis and 19 body mass index-, age-, and sex-matched controls. In addition, hepatic mRNA expression was assessed by qPCR in livers of seven patients with cirrhosis and four controls. Circulating visfatin was 78% lower in cirrhotics (P < 0.001) and decreased with worsening of the clinical stage of liver disease. Hepatic visfatin secretion decreased with clinical stage (P < 0.05) and reduced liver function (P = 0.01). Consistent with these data, hepatic visfatin mRNA expression was significantly lower in cirrhotic livers (P < 0.05). Circulating visfatin in cirrhosis was correlated with body cell mass (r = 0.72, P < 0.01) as well as with body fat mass (r = 0.53, P < 0.05) but not with plasma glucose, insulin, the degree of insulin resistance, or whole body glucose oxidation rates. Higher visfatin levels were associated with higher hepatic glucose production (r = 0.53, P < 0.05) and also with a higher arterial ketone body ratio (KBR) (r = 0.48, P < 0.05), an indicator of increased hepatic NAD generation. In conclusion, circulating visfatin levels are significantly decreased in liver cirrhosis, presumably attributable to decreased hepatic expression and production. Plasma visfatin in cirrhosis is not associated with insulin resistance but correlates with hepatic glucose production and the arterial KBR, indicating a potential link between the NAD-generating properties of visfatin and metabolism. adipokines; human; metabolism; nicotinamide phosphoribosyltransferase; pre-B cell colony-enhancing factor

The adipokine resistin has been implicated in obesity and insulin resistance. Liver cirrhosis is associated with decreased body fat mass and insulin resistance. We determined plasma resistin levels in 57 patients with cirrhosis, 13 after liver transplantation, and 30 controls and correlated these with hemodynamic as well as hepatic and systemic metabolic parameters. Patients with cirrhosis had, dependent on the clinical stage, an overall 86% increase in resistin levels (P < 0.001) with hepatic venous resistin being higher than arterial levels (P < 0.001). Circulating resistin was significantly correlated with plasma TNF-[alpha] levels (r = 0.62, P < 0.001). No correlation was observed between resistin and hepatic hemodynamics, body fat mass, systemic energy metabolism, and the degree of insulin resistance. However, plasma resistin in cirrhosis was negatively associated with hepatic glucose production (r = -0.47, P < 0.01) and positively with circulating free fatty acids (FFA; r = 0.40, P < 0.01) and ketone bodies (r = 0.48, P < 0.001) as well as hepatic ketone body production (r = 0.40, P < 0.01). After liver transplantation, plasma resistin levels remained unchanged, whereas insulin resistance was significantly improved (P < 0.01). These data provide novel insights into the role of resistin in the pathophysiological background of a catabolic disease in humans and also indicate that resistin inhibition may not represent a suitable therapeutic strategy for the treatment of insulin resistance and diabetes in patients with liver cirrhosis. hepatic turnover; body composition; liver; portal pressure doi:10.1152/ajpendo.00291.2005

Adiponectin is a novel adipocytokine negatively correlated with parameters of the metabolic syndrome, such as body mass index (BMI), body fat mass (BFM), and circulating insulin levels. Furthermore, metabolic actions directly on the liver have been described. The aim of the present study was to characterize circulating adiponectin levels, hepatic turnover, and the association of adiponectin with key parameters of hepatic as well as systemic metabolism in cirrhosis, a catabolic disease. Circulating adiponectin levels and hepatic turnover were investigated in 20 patients with advanced cirrhosis. Hepatic hemodynamics [portal pressure, liver blood flow, hepatic vascular resistance, indocyanine green (ICG) half-life], body composition, resting energy expenditure, hepatic free fatty acids (FFA) and glucose turnover, and circulating levels of hormones (catecholamines, insulin, glucagon) and proinflammatory cytokines (IL-1[beta], TNF-[alpha], IL-6) were also assessed. Circulating adiponectin increased dependently on the clinical stage in cirrhosis compared with controls (15.2 [+ or -] 1.7 vs. 8.2 [+ or -] 1.1 [micro]g/ml, respectively, P < 0.01), whereas hepatic extraction decreased. Adiponectin was negatively correlated with parameters of hepatic protein synthesis (prothrombin time: r = -0.62, P - 0.003; albumin: r = -0.72, P < 0.001) but not with transaminases or parameters of lipid metabolism. In addition, circulating adiponectin increased with portal pressure (r = 0.67, P = 0.003), hepatic vascular resistance (r = 0.60, P = 0.008), and effective hepatic blood flow (ICG half-life: r = 0.69, P = 0.001). Adiponectin in cirrhosis was not correlated with BMI, BFM, parameters of energy metabolism, insulin levels, hepatic FFA and glucose turnover, and circulating proinflammatory cytokines. These results demonstrate that 1) adiponectin plasma levels in cirrhosis are significantly elevated, 2) the liver is a major source of adiponectin extraction, and 3) adiponectin levels in cirrhosis do not correlate with parameters of body composition or metabolism but exclusively with reduced liver function and altered hepatic hemodynamics. hepatic turnover; hepatic venous pressure gradient; calorimetry; body composition

The acute-phase protein secretory phospholipase A2 ([sPLA.sub.2]) influences the metabolism of high-density lipoproteins (HDL). The adrenals are known to utilize HDL cholesterol as a source of sterols. The aim of the present study was to test the hypothesis that [sPLA.sub.2] enhances the selective uptake of HDL into the adrenals in response to acute inflammation as a possible physiological role for the [sPLA.sub.2]-HDL interaction. Human [sPLA.sub.2]-transgenic mice, in which [sPLA.sub.2] expression is upregulated by inflammatory stimuli, were used. Ten hours after induction of the acute-phase response (APR) by injection of bacterial lipopolysaccharide (LPS), plasma levels of HDL cholesterol decreased significantly in [sPLA.sub.2]-transgenic mice (-18%, P < 0.05) but remained unchanged in wild-type mice. The fractional catabolic rates of both [sup.125]I-labeled tyramine-cellobiose (TC)-HDL and [[sup.3]H]cholesteryl ether increased significantly in the [sPLA.sub.2]-transgenic mice after induction of the APR (0.18 [+ or -] 0.01 vs. 0.21 [+ or -] 0.01 pool/h, P < 0.05, and 0.31 [+ or -] 0.02 vs. 0.42 [+ or -] 0.05 pool/h, P < 0.05, respectively) but remained unchanged in the wild-type mice (0.10 [+ or -] 0.01 vs. 0.22 [+ or -] 0.02 pool/h, respectively). After induction of the APR, in both groups HDL holoparticle uptake by the liver was increased (P < 0.001). [sPLA.sub.2]-transgenic mice had 2.4-fold higher selective uptake into the adrenals after induction of the APR than wild-type mice (156 [+ or -] 6 vs. 65 [+ or -] 5%/[micro]g tissue protein, P < 0.001). In summary, upregulation of [sPLA.sub.2] expression during the APR specifically increases the selective uptake of HDL cholesteryl ester into the adrenals. These data suggest a novel metabolic role for [sPLA.sub.2]: modification of HDL during the APR to promote increased adrenal uptake of HDL cholesteryl ester to serve as source for steroid hormone synthesis. apolipoproteins; lipoproteins; kinetics; acute-phase response; lipopolysaccharide