Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. METHODS AND RESULTS: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001). CONCLUSIONS: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.

Genetic and environmental determinants of the PON-1 phenotype.

BACKGROUND: Paraoxonase (PON-1) is a high-density lipoprotein (HDL)-associated enzyme that may protect against cardiovascular disease (CVD), because it hydrolyses oxidized phospholipids of low-density lipoprotein (LDL) and therefore prevents the detrimental effects on the arterial wall. The current report describes the determinants of PON-1 bioavailability and activity. MATERIALS AND METHODS: This is the largest (n = 1527) cross-sectional evaluation performed on PON-1 genotypes (Q192R, T-107C and L55M) and environmental determinants to PON-1 catalytic activity and bioavailability in serum of postmenopausal women. PON-1 catalytic activity and PON-1 bioavailability were measured, in vitro, with a paraoxon hydrolysis assay and a phenylacetate hydrolysis assay, respectively. RESULTS: The major determinant of paraoxon hydrolytic activity is the Q192R genotype, but there was also a relation with the C-107T and L55M genotype, HDL levels and alcohol consumption. Phenylacetate hydrolytic activity was most strongly affected by the C-107T genotype followed by the L55M genotype, HDL levels, alcohol consumption and smoking. CONCLUSIONS: PON-1 Q192R, C-107T and L55M genotype, alcohol consumption, smoking and HDL levels are determinants of serum PON-1 phenotype. The contributions of the genetic markers to the PON-1 phenotype are stronger than the contributions of the lifestyle determinants.

The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine.

Since the discovery of human serum paraoxonase (PON1), the enzyme has been the subject of various fields of research. Initially, PON1 was identified as an enzyme capable of hydrolysing organophosphate compounds, but there is a growing body of evidence that PON1 plays a role in lipid metabolism and the onset of cardiovascular disease. Still, the precise mechanism by which PON1 functions in vivo remains to be clarified. Here we will briefly review developments in the field of PON1 research which merit further attention.

Proportion of oxidized LDL relative to plasma apolipoprotein B does not change during statin therapy in patients with heterozygous familial hypercholesterolemia.

OBJECTIVE: Circulating oxidized low-density lipoprotein (LDL) has been shown to be a useful marker for identifying patients with coronary heart disease (CHD) and persons at high cardiovascular risk. The effect of cholesterol-lowering therapy on plasma level of oxidized LDL is not clear. METHODS AND RESULTS: We investigated effects of cholesterol lowering by therapeutic intervention (2 years) with atorvastatin (80 mg daily) and simvastatin (40 mg daily) on circulating oxidized LDL (absolute level and in proportion to plasma apolipoprotein B) in relation to atherosclerosis progression (carotid intima-media thickness, carotid IMT) and to inflammation (high-sensitivity C-reactive protein, hsCRP) in 115 stable patients with heterozygous familial hypercholesterolemia (FH). Atorvastatin and simvastatin reduced plasma-oxidized LDL (-43 and -35%, respectively) in proportion to the decrease in plasma apolipoprotein B. Neither absolute nor relative level of oxidized LDL correlated with carotid IMT or hsCRP at baseline. Also changes in levels of circulating oxidized LDL were not related to changes in carotid IMT and hsCRP. CONCLUSIONS: In familial hypercholesterolemia-oxidized LDL carried in plasma is strongly associated with apolipoprotein B but not with inflammation nor with carotid IMT, and statin treatment does not reduce oxidized LDL relative to apolipoprotein B.

Development of a rapid identification method for Klebsiella pneumoniae phylogenetic groups and analysis of 420 clinical isolates.

A rapid method combining gyrA PCR-restriction fragment length polymorphism analysis, parC PCR and adonitol fermentation was developed to identify Klebsiella pneumoniae phylogenetic groups KpI, KpII and KpIII. Analysis of 420 clinical isolates from 26 hospitals showed that the three groups were widespread geographically. KpI comprised 80.3% of 305 isolates from blood and 82.2-97.2% of isolates from other clinical sources. KpIII was never found among isolates from urinary tract infections. KpI isolates from blood were generally less susceptible than KpIII isolates to the ten antimicrobial agents tested, with KpII being intermediate. The frequencies of ceftazidime resistance were 21.6% and 8.6% in KpI and KpIII isolates, respectively (p 0.01).