NMR-based metabonomic analysis is a well-established approach to characterizing healthy and diseased states. The aim of this study was to investigate inter-individual variability in the metabolic urinary profile of a healthy Greek population, not subjected to strict dietary limitations, by NMR-based metabonomics. The overall metabonomic urinalysis showed a homogeneous distribution among the population. The metabolic profile was examined in relation to gender and age, and reference intervals of major metabolites were determined. Multivariate data analysis led to the construction of two robust models that were able to predict the class membership of the subjects studied according to their gender and age. The most influential low molecular weight metabolites responsible for the differences in gender groups were citrate, creatinine, trimethylamine N-oxide, glycine, creatine and taurine, and for the differences in age groups they were citrate, creatinine, trimethylamine N-oxide and an unidentified metabolite (d 3.78).

Abstract-Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase A 2 that is primarily associated with low density lipoprotein (LDL). PAF-AH activity has also been found in high density lipoprotein (HDL), although it has recently been indicated that there is no PAF-AH protein in HDL. Plasma paraoxonase 1 (PON1) is an HDL-associated esterase, which also exhibits PAF-AH-like activity. The effect of atorvastatin (20 mg per day for 4 months) on PAF-AH and PON1 activities in patients with dyslipidemia of type IIA (nϭ55) or type IIB (nϭ21) was studied. In both patient groups, atorvastatin significantly reduced plasma PAF-AH activity because of the decrease in LDL plasma levels and the preferential decrease in PAF-AH activity on dense LDL subfractions (LDL-4 and LDL-5). Drug therapy did not affect HDL-associated PAF-AH activity or serum PON1 activities toward paraoxon and phenylacetate in either patient group. However, because of the reduction in LDL cholesterol levels, the ratios of HDL-associated PAF-AH and serum PON1 activities to LDL cholesterol levels were significantly increased after drug administration. The reduction of the LDL-associated PAF-AH activity and the elevation in the ratios of HDL-associated PAF-AH and PON1 activities to LDL plasma levels may represent a new dimension in the antiatherogenic effect of atorvastatin. Key Words: hyperlipidemia Ⅲ monocytes/macrophages Ⅲ platelet-activating factor acetylhydrolase Ⅲ paraoxonase Ⅲ atorvastatin P latelet-activating factor (PAF) is a potent lipid mediator involved in inflammatory diseases 1 as well as in atherogenesis. 2 In plasma, PAF is hydrolyzed and inactivated by PAF-acetylhydrolase (PAF-AH, EC 3.1.1.47), a Ca 2ϩ -independent phospholipase A 2 . 3 PAF-AH has a marked preference for phospholipids with short-chain moieties at the sn-2 position, and with the exception of PAF, PAF-AH can equally hydrolyze oxidized phospholipids containing a polyunsaturated fatty acyl residue at this position. 3 Plasma PAF-AH is complexed to lipoproteins 4,5 ; thus, it is also denoted as lipoprotein-associated phospholipase A 2 . 6 The role of this enzyme in inflammatory and atherosclerotic diseases remains to be established. Indeed, PAF-AH may represent a potent anti-inflammatory and antiatherogenic enzyme because it degrades PAF and proinflammatory oxidized phospholipids, molecules formed during the oxidation of LDL. 7 Consistent with the hypothesis that PAF-AH may exert a cardioprotective role are clinical studies showing that loss of plasma PAF-AH activity due to a G9943 T mutation in the PAF-AH gene may constitute a genetic determinant of atherosclerotic disease in the Japanese population. 8 In contrast to these findings, PAF-AH may exert proinflammatory and proatherogenic actions as a result of the hydrolysis of oxidized phospholipids, because bioactive oxidized free fatty acids 6 and lysophosphatidylcholine are generated. 9,10 A recent clinical study indicating that the mass of plasma PAF-AH could be a potential risk factor for coronary a...

Objective: The significance of dyslipidemia in subclinical hypothyroidism (SH) and the effect of thyroid substitution on lipids remain controversial. The present study aimed to assess the association of SH with lipid abnormalities and to quantify the effect of L-thyroxine therapy on serum lipid profiles. Design: Serum lipid parameters of 66 patients with SH and 75 age-and sex-matched euthyroid controls were evaluated in a cross-sectional study. Results: Patients with SH had higher total cholesterol (TC) ð222^45 (S.D.) vs 190^32 mg=dlÞ; lowdensity lipoprotein cholesterol (LDL-C) ð139^28 vs 118^39 mg=dlÞ; apolipoprotein B ð149^21 vs 139^18 mg=dlÞ and lipoprotein (a) (Lp(a)) (median 12.5 (0.8-101) mg/dl vs 7 (0.8 -44) mg/dl) levels compared with euthyroid controls (P , 0:05 for all comparisons). In a follow-up study including 37 patients with SH, all measurements were repeated after restoration of a euthyroid state with incremental doses of L-thyroxine. No significant changes in serum lipid profiles were observed except for a decrease in high-density lipoprotein cholesterol ð59^15 to 55^14 mg=dl; P , 0:05Þ: However, patients with high pre-treatment TC ($240 mg/dl) showed a significant reduction in both TC ð278^28 vs 257^36 mg=dl; P , 0:05Þ and LDL-C ð192^23 vs 173^28 mg=dl; P , 0:01Þ levels. Similar but more pronounced changes were observed in a subgroup of patients with pre-treatment levels of TSH $10 mU/ml. Thyroid autoimmunity had no effect on either the baseline or the posttreatment lipid profile. Conclusion: Although patients with subclinical hypothyroidism exhibit increased levels of the atherogenic parameters (mainly LDL-C and Lp(a)), thyroid substitution therapy does not seem to significantly improve dyslipidemia in the whole group of patients.

The frequency of ischaemic heart disease observed after splenectomy for trauma and the low cholesterol levels found in patients with hypersplenism are observations that suggest a possible role for the spleen in lipid metabolism and in the aetiology of atherosclerosis. The present study was designed to examine this role in experimental animals. Serum levels of total cholesterol, triglyceride and high-density lipoprotein (HDL) cholesterol were determined in 32 rats. The spleen was removed in 16 rats and the remaining 16 were sham operated. Half of the splenectomized and half of the remaining rats were fed on a diet rich in fat and the two other subgroups were fed normal chow. Blood tests were performed before, and 3 and 6 months after operation. A significant increase in serum triglyceride and decrease in serum HDL cholesterol levels was observed after splenectomy in rats fed normal chow compared with sham-operated rats. An increase in serum triglyceride and a decrease in serum HDL cholesterol levels was observed in both groups of rats fed normal chow plus high-fat cheese. However, these changes were more pronounced in splenectomized rats. These findings suggest that the spleen has a role in lipid metabolism in rats and may therefore influence atherosclerosis.

Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated mainly with the apolipoprotein B (apoB)-containing lipoproteins and primarily with LDL. A small proportion of enzymatic activity is also associated with HDL. Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. The effect of fenofibrate on PAF-AH and PON1 activities in patients with dyslipidemias of Types IIA, IIB, and IV were studied. Fenofibrate reduced plasma PAF-AH activity in all patient groups. In Type IIA patients, this reduction was mainly due to a fall in enzyme activity associated with the dense LDL subspecies, whereas in Type IIB and Type IV patients, it was due to the decrease in PAF-AH activity associated with both the VLDL ؉ IDL and dense LDL subspecies. Drug therapy in Type IIB and Type IV patients significantly increased the HDL-associated PAF-AH activity due to the increase in enzyme activity associated with the HDL-3c subfraction. Fenofibrate did not affect serum PON1 activities toward paraoxon and phenylacetate in either patient group.The fenofibrate-induced elevation of HDL-associated PAF-AH activity in dyslipidemic patients of Type IIB and Type IV, as well as the reduction in enzyme activity associated with atherogenic apoBcontaining lipoproteins in all patient groups, may represent a new and important antiatherogenic effect of this potent lipid-modulating agent.