To evaluate the feasibility of using [18F]fluorodeoxyglucose positron emission tomographycomputed tomography (FDG-PET/CT) to detect and quantify systemic inflammation in patients with psoriasis.Design: Case series with a nested case-control study.Setting: Referral dermatology and preventive cardiology practices.Participants: Six patients with psoriasis affecting more than 10% of their body surface area and 4 controls age and sex matched to 4 of the patients with psoriasis for a nested case-control study. Main Outcome Measures:The FDG uptake in the liver, musculoskeletal structures, and aorta measured by mean standardized uptake value, a measure of FDG tracer uptake by macrophages and other inflammatory cells.Results: FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. Inflammation in the joints

Objectives Psoriasis is a Th-1/17 mediated inflammatory disease associated with increased risk of cardiovascular disease (CVD). Inflammation may modulate lipoprotein particle number and directly impair HDL functions, in particular reverse cholesterol transport (RCT). We sought to study how chronic in vivo inflammation modulates lipoprotein particle composition using nuclear magnetic resonance spectroscopy (NMR) and HDL efflux in psoriasis. Methods and Results We prospectively enrolled a consecutive sample of patients with psoriasis (n=122) and compared lipoprotein and metabolic risk factors to patients without psoriasis (n=134). Fasting lipids, insulin, glucose were measured by standard assays, and lipoprotein concentration and size were measured by NMR. In a random subset (n=100 each group), HDL efflux capacity was quantified using a validated ex vivo system involving the incubation of macrophages with apolipoprotein B-depleted serum from patients. Traditional lipid concentrations were similar in both groups except for HDL concentration which was lower in psoriasis (43 mg/dL (36–58) vs 50 (42–62), p<0.01). However, NMR showed an atherogenic profile in psoriasis similar to that observed in diabetes, with significant increase in LDL particle concentration [1210.5 (1002–1498) vs 1115 (935–1291), p=0.03] with decrease in LDL size [20.6 (20.3–21.1) vs 21.3 (20.6–21.1), p<0.001] beyond CV risk factors and HOMA-IR (p=0.001). Finally, HDL efflux capacity was lower in psoriasis compared to controls in fully adjusted models (beta −0.14, p=0.001). Conclusions These data support a more atherogenic lipoprotein profile by NMR and decreased HDL efflux capacity in psoriasis patients compared to controls beyond CVD risk factors. The abnormal lipoprotein particle composition and HDL efflux capacity in psoriasis may provide a link between psoriasis and CVD.

Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1.

Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma protein that promotes the bidirectional transfer of cholesteryl esters (CE) and triglycerides (TG) between and among HDL particles and atherogenic apolipoprotein B-containing (ApoB-containing) lipoproteins, including the predominantly TG-rich VLDL, intermediate-density lipoprotein (IDL), and LDL particles (1-3). Genetic deficiency of CETP is associated with elevated HDL cholesterol (HDL-C) and reduced LDL-C (1), and common variants at the CETP locus are associated with HDL-C and LDL-C in inverse directions (3). Pharmacologic inhibition of CETP activity in humans raises HDL-C levels and generally reduces LDL-C levels (4-7).The mechanism by which CETP inhibition reduces LDL-C remains unknown. A study of ApoB kinetics during administration of the CETP inhibitor torcetrapib (120 mg), with or without atorvastatin (ATV), to subjects with dyslipidemia (8) suggested that in dyslipidemic subjects, torcetrapib monotherapy reduced LDL ApoB by increasing the fractional catabolic rate (FCR) and that torcetrapib administered with ATV may have reduced production of LDL ApoB. However, none of these changes were statistically significant. Thus, the study was underpowered for detecting changes in many of the ApoB kinetic parameters and led to no firm conclusions regarding the mechanisms responsible for the lowering of ApoB.BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib. METHODS.We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR). RESULTS.Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR. CONCLUSION.These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance. TRIAL REGISTRATION. ClinicalTrials.gov NCT00990808.

Objective Anacetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of HDL-C, apoA-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo-controlled, double-blind, fixed-sequence study to examine the effects of anacetrapib on the metabolism of HDL apoA-I and apoA-II and plasma CETP. Approach and Results Twenty-nine participants received atorvastatin 20mg/day plus placebo for four weeks, followed by atorvastatin plus anacetrapib 100 mg/day for 8 weeks (ATV-ANA). Ten participants received double placebo for four weeks followed by placebo plus anacetrapib for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, anacetrapib treatment increased plasma HDL-C (63.0%, P < 0.001) and apoA-I levels (29.5%, P < 0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (FCR) (18.2%, P = 0.002) without changes in production rate (PR). Although the apoA-II levels increased by 12.6% (P < 0.001), we could not discern significant changes in either apoA-II FCR or PR. CETP levels increased 102% (P < 0.001) on anacetrapib due to a significant reduction in the FCR of CETP (57.6%, P < 0.001) with no change in CETP PR. Conclusion Anacetrapib treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808