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Background: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters., Methods: We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1)., Findings: HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman's correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=-0.59, p=0.0065) insulin sensitivity., Conclusions: Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Background: Accumulating data suggest a novel role for bile acids (BAs) in modulating metabolic homeostasis. BA treatment has been shown to improve glucose tolerance and to increase energy expenditure in mice. Here, we investigated the relationship between fasting plasma BAs concentrations and metabolic parameters in humans., Findings: Fasting plasma glucose, insulin and lipid profile were measured in 14 healthy volunteers, 20 patients with type 2 diabetes (T2D), and 22 non-diabetic abdominally obese subjects. Insulin sensitivity was also assessed by the determination of the glucose infusion rate (GIR) during a hyperinsulinemic-euglycemic clamp in a subgroup of patients (9 healthy and 16 T2D subjects). Energy expenditure was measured by indirect calorimetry. Plasma cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) concentrations were analyzed by gas chromatograph-mass spectrometry. In univariable analysis, a positive association was found between HOMA-IR and plasma CDCA (β = 0.09, p = 0.001), CA (β = 0.03, p = 0.09) and DCA concentrations (β = 0.07, p < 0.0001). Spearman analysis retrieved an inverse relationship between plasma CDCA (r = -0.44, p = 0.03), CA (r = -0.65, p = 0.001) and the GIR. HOMA-IR remained positively associated with CDCA (β = 0.11, p = 0.01), CA (β = 0.04, p = 0.01) and DCA (β = 0.06, p = 0.007) in multivariable analysis, after adjustment for age, gender, BMI, HbA1C and plasma lipid parameters. In contrast, HbA1c, energy expenditure and plasma lipid concentrations were not correlated with plasma BAs levels in multivariable analysis., Conclusions: Both plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a wide range of subjects.

Objective: Proprotein convertase subtilisin kexin/type 9 (PCSK9) is an inhibitor of the low density (LDL) lipoprotein receptor. Plasma PCSK9 is increased by fenofibrate and statins. Here, we determined how standard dose of statin and combined therapy with fenofibrate modulate PCSK9., Methods: Randomized, open-label cross-over study investigating the effect of fenofibrate (160 mg), atorvastatin (10 mg), and combination of both in patients with type 2 diabetes mellitus and atherogenic dyslipidemia. After the single administration of atorvastatin and fenofibrate for 6 weeks, patients received both for another 6 weeks. PCSK9, lipids and lipoproteins levels were determined at day 1, weeks 6, 9 and 12., Results: Upon 6 weeks of treatment, atorvastatin decreased LDL-cholesterol by 30% (p<0.001) and fenofibrate decreased triglyceride level by 31% (p<0.01) and increased HDL-cholesterol by 13% (p<0.05). Combination did not show further benefit. Atorvastatin increased PCSK9 by 24% at day 1 and by 14% at week 6 (p < or = 0.01). Fenofibrate increased PCSK9 by 26% at week 6 (p < or = 0.01), but had no effect at day 1. Three weeks of combination therapy increased PCSK9 by 42%, 6 weeks by 19% (p < or = 0.01). PCSK9 changes were not different between treatments over 6-week periods., Conclusion: Fenofibrate and atorvastatin increased circulating PCSK9 in diabetic patients, with no additive effect after 6 weeks of combined therapy., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a secreted proprotein convertase acting as a natural inhibitor of the low-density lipoprotein (LDL) receptor. Here, we prospectively investigated the relationship between the circulating levels of PCSK9 and metabolic parameters in 117 diabetic patients., Results: Plasma PCSK9 level was significantly higher in type 2 than in type 1 diabetes (P=0.04), in diabetic patients under statins (P<10(-4)) and in those with macrovascular complications (P=0.002). Univariable regression analysis revealed that plasma PCSK9 level correlated positively with age (P=0.003), body mass index (P=0.04), systolic blood pressure (SBP) (P=0.01), gamma-glutamyl transferase (GGT) levels (P=0.0002) and statin treatment (P=0.001). In a multivariable linear regression analysis, PCSK9 correlated positively with GGT level (beta=21.91, P=0.0019) after adjustment for gender, age, type of diabetes, statin treatment, BMI, SBP and HbA1c., Conclusion: PCSK9 level was independently associated with GGT level in diabetic patients, suggesting potential interaction between PCSK9 and liver function., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)