Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets

Abstract

BackgroundPCSK9 (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.MethodsWe 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).FindingsHF 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.ConclusionsPlasma 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.

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

“…It has been shown that circulating PCSK9 levels relate to insulin and glucose levels ( 7,8,28 ). This was confi rmed in the present study.…”

“…Based on their reported menses, these subjects were further divided into three groups ( 23 ): follicular phase (days 1-11), ovulation phase (days [12][13][14][15][16][17][18], and luteal phase (days [19][20][21][22][23][24][25][26][27][28][29][30][31][32]. As expected, the E2 level was highest at ovulation ( Fig.…”

Potential of PCSK9 as a new target for the management of LDL cholesterol

“…Recent intriguing studies have identified a direct association with plasma triglycerides, suggesting a potential effect of PCSK9 on triglyceride-rich lipoproteins. 16,17 Confirming this observation, subjects carrying a PCSK9 gain-of-function mutation showed a three-fold elevation in apolipoprotein (apo)B100 production rates compared with normal subjects. 18 Chan et al found that PCSK9 and apoC-III are inversely associated with the catabolic rate of triglyceride-rich lipoprotein-apoB48, suggesting a role of PCSK9 in the post-prandial coordination of the catabolism of this lipoprotein.…”

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial

“…In contrast, the ILLUMINATE study [22] found that plasma PCSK9 levels were elevated in patients with DM compared with those without DM, with a significant association between PCSK9 levels and LDL-C, TGs, glucose, insulin and homoeostasis model assessment of insulin resistance (HOMA-IR) scores. In addition, a study evaluating the impact of a short-term high-calorie, high-fructose diet showed that plasma PCSK9 levels were increased with this diet independently of cholesterol synthesis, and associated with insulin resistance, hepatic steatosis and TG levels [23]. Thus, the potential interaction between PCSK9 inhibitors and exogenously administered insulin is of considerable interest.…”

“…Separate analyses will be performed for patients with T1DM and T2DM, with an overall analysis of all participants for some efficacy endpoints. The percentage change in calculated LDL-C from baseline to week 24 will be analyzed using a mixed-effect model with repeated measures (MMRM) approach to account for any missing data, using all available post-baseline data within the analysis windows (weeks [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. The model will also include fixed categorical effects of treatment group, time point and treatment-by-time interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline value-by-time point interaction.…”