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Potential discrepancies between laboratory and estimated (from Continuous Glucose Monitoring (CGM)) glycated hemoglobin (HbA1c) have been reported by diabetologists. CGM devices produce an eA1c derived from average glucose and correlated with Time-in-Range (TIR, %) which is the relative time spent in a range of normal glycaemia. Through a case report, we studied the potential causes for these discrepancies. CGM devices estimate eA1c during the lifespan of the sensor, that is replaced every 14 days and HbA1c is a retrospective data of exposure to hyperglycemia over 8 to 12 weeks. In our case report, the patient had a poor glycemic control resulting in 9% eA1c compared to 7,4% HbA1c got by delocalized immune-assay (Siemens DCA-Vantage®), confirmed at 7,7% by HPLC (Variant II Turbo). On top of the CGM data, an increased labile A1c (LA1c) fraction was found on the patient's HbA1c HPLC profile, both in favor of a recently altered glycemic control. Thus, recent and/or substantial variations in glycemic control will increase the gap between HbA1c and eA1c, being a potential source of therapeutic errors. The differences of those markers, particularly the time window during which it is estimated, make them hardly comparable. As the use of CGM is becoming widespread, it is important to understand and harness its data and biomarkers.

International audience; Background & aims: Blond orange juice is the most consumed fruit juice in the world. It is a source of hesperidin, a bioavailable flavonoid reported to exhibit potential vascular protective actions. However, the specific impact on vascular function of Citrus phytomicronutrients, is unknown. For the first time, we investigated the effects of blond orange juice compared with a control beverage mimicking the composition of orange juice (including Vitamin C but no phytomicronutrients), on antioxidant markers, cardiovascular risk factors and endothelial function. Methods: Twenty five male volunteers with two cardiovascular risk factors (age over 50 years and LDL-cholesterol between 130 and 190 mg/L) were enrolled in a randomized cross-over study. They received 3 times daily 200 mL of either blond orange juice or control beverage for 4 weeks, spaced by a 5-week wash-out. Endothelial function (flow mediated dilatation and plasma markers), oxidative status, lipid profile and inflammatory markers were assessed. Results: Daily intakes of orange juice significantly led to a marked antioxidant effect which was correlated to hesperetin plasma levels and related with a decrease in reactive oxygen species. A tendency towards reduction of endothelial dysfunction and modest increase in plasma apoA-I concentration were also observed. This allows further experiments demonstrating the specific effect of phytomicronutrients from orange juice. Conclusions: These findings suggest that daily intake of nutritionally relevant dose of blond orange juice may contribute for a significant antioxidant effect through the phytochemicals contained in. Orange juice may be associated to other healthy foods to achieve a significant effect on the vascular function. This study is recorded in ClinicalTrials.com as NCT00539916. (C) 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis. The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined. Herein, we studied the role of CD154, a key mediator of inflammation, in hepatic steatosis. To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil. In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines. Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins. This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2α. Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments. Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1. The control of the UPR by CD154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis. Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis. (HEPATOLOGY 2010)

Carboxylic acid haptens were synthesised, for Hesperetin ( Hesp ) and Naringenin ( Nar ). They had a spacer arm (4 or 6 carbons long) on the C7 position. Haptens were coupled to bovine serum albumin. Polyclonal antibodies were generated. Enzyme-linked immunosorbent assays (ELISAs) were developed. Owing to sensitivity, one antibody for each flavanone was retained, namely anti- h4-Hesp and anti- h4-Nar . For Hesp and Nar, IC 50 of the standard curves were 1.29 pmol/well and 0.72 pmol/well, respectively. Intra-assay and inter-assay variations were 10.24% and 10.53%, respectively for Hesp and 10.03% and 10.79%, respectively for Nar . Anti- h4-Hesp was highly specific when anti-h4-Nar showed cross-reactions with liquiritigenin and eriodictyol, which were significantly reduced in heterologous assay conditions. Assays were validated by comparisons with HPLC Coularray. Measurements were done on diet, plasma and urine samples from mice fed on diets enriched with Hesp or Nar and on a range of diluted mice urine samples.

Flavanones are found specifically and abundantly in citrus fruits. Their beneficial effect on vascular function is well documented. However, little is known about their cellular and molecular mechanisms of action in vascular cells. The goal of the present study was to identify the impact of flavanone metabolites on endothelial cells and decipher the underlying molecular mechanisms of action. We investigated the impact of naringenin and hesperetin metabolites at 0·5, 2 and 10 μm on monocyte adhesion to TNF-α-activated human umbilical vein endothelial cells (HUVEC) and on gene expression. Except hesperetin-7-glucuronide and naringenin-7-glucuronide (N7G), when present at 2 μm, flavanone metabolites (hesperetin-3′-sulphate, hesperetin-3′-glucuronide and naringenin-4′-glucuronide (N4′G)) significantly attenuated monocyte adhesion to TNF-α-activated HUVEC. Exposure of both monocytes and HUVEC to N4′G and N7G at 2 μm resulted in a higher inhibitory effect on monocyte adhesion. Gene expression analysis, using TaqMan Low-Density Array, revealed that flavanone metabolites modulated the expression of genes involved in atherogenesis, such as those involved in inflammation, cell adhesion and cytoskeletal organisation. In conclusion, physiologically relevant concentrations of flavanone metabolites reduce monocyte adhesion to TNF-α-stimulated endothelial cells by affecting the expression of related genes. This provides a potential explanation for the vasculoprotective effects of flavanones.

Lecithin cholesterol acyltransferase (LCAT) is a key enzyme which catalyzes the esterification of free cholesterol present in plasma lipoproteins. In order to evaluate the role of LCAT in HDL metabolism, a 6.2-kilobase (kb) fragment consisting of 0.851 and 1.134 kb of the 5'- and 3'-flanking regions, as well as the entire human LCAT gene, was utilized to develop transgenic mice. Three different transgenic mouse lines overexpressing human LCAT at plasma levels 11-, 14-, and 109-fold higher than non-transgenic mice were established. Northern blot hybridization analysis demonstrated that the injected 6.2-kb fragment contained the necessary DNA sequences to direct tissue specific expression of the human LCAT gene in mouse liver. Compared to age- and sex-matched controls, total cholesterol and HDL cholesterol levels were increased in all 3 transgenic mice lines by 124-218 and 123-194%, respectively, while plasma triglyceride concentrations remained similar to that of control animals. Fast protein liquid chromatography analysis of transgenic mouse plasma revealed marked increases in high density liposportin (HDL)-cholesteryl ester and phospholipid as well as the formation of larger size HDL. Thus, the majority of the increase in transgenic plasma cholesterol concentrations was due to accumulation of cholesteryl ester in HDL consistent with enhanced esterification of free cholesterol in mouse HDL by human LCAT. Plasma concentrations of apoA-I, apoA-II, and apoE were increased in high expressor homozygote mice who also demonstrated an accumulation of an apoE-rich HDL1. Like the mouse enzyme, human LCAT was found to be primarily associated with mouse HDL. Our studies demonstrate a high correlation between plasma LCAT activity and total as well as HDL cholesterol levels establishing that in mice LCAT modulates plasma HDL concentrations. Overexpression of LCAT in mice leads to HDL elevation as well as increased heterogeneity of the HDL lipoprotein particles, indicating that high levels of plasma LCAT activity may be associated with hyperalphalipoproteinemia and enhanced reverse cholesterol transport.

Publication Inra prise en compte dans l'analyse bibliométrique des publications scientifiques mondiales sur les Fruits, les Légumes et la Pomme de terre. Période 2000-2012. http://prodinra.inra.fr/record/256699; International audience; Naringin (NAR) from grapefruit has exhibited potential protective effects against atherosclerosis development However, specific mechanisms responsible for such effects are poorly understood. Thus, we aimed to investigate the antiatherogenic effects of NAR in different mouse models of hypercholesterolemia and decipher its molecular targets in the aorta using transcriptomic approach. Two mouse models of hypercholesterolemia, wild-type mice fed a high-fat/high-cholesterol diet and apolipoprotein E-deficient mice fed a semisynthetic diet, were studied. Mice were fed a respective control diets supplemented or not for 18 weeks with 0.02% of NAR, that is, nutritional supplementation. NAR supplementation reduced plaque progression only in wild-type mice fed the high-fat/high-cholesterol diet (-41%). Consistent with this protective effect, NAR reduced plasma non-high-density lipoprotein cholesterol concentrations as well as biomarkers of endothelial dysfunction. Microarray studies performed on aortas demonstrated differentially expressed genes encoding proteins involved in cell adhesion, actin cytoskeleton organization and cell division. Thus, the changes in gene expression induced by NAR could suggest a limited atherosclerosis progression by preventing immune cell adhesion and infiltration in the intima of vascular wall, as well as smooth muscle cell proliferation. Furthermore, this hypothesis was strengthened by in vitro experiments, which showed the ability of naringenin to reduce monocyte adhesion to endothelial cells and smooth muscle cell proliferation. In conclusion, this study revealed the antiatherogenic effect of NAR supplemented at a nutritionally achievable dose, specifically toward diet-induced atherosclerosis, and depicted its multitarget mode of action at the vascular level. (C) 2012 Elsevier Inc. All rights reserved.

Epidemiological and clinical studies a role for flavanones (predominately found in citrus fruits) in the prevention of cardiovascular disease. Previously, we have shown that a nutritional dose of naringin exerts anti-atherogenic properties together with non HDL-cholesterol lowering effect in a murin model of dietary-induced hypercholesterolemia (1). The goal of the present study was to explore possible molecular mechanisms of naringin at the hepatic level. To this end, we analyzed the hepatic transcriptome using a microarray approach in response to naringin supplementation (0.02%) in mice fed a high-fat high- cholesterol diet. Naringin was observed to increase hepatic lipid content (triglyceride and cholesterol) without significant liver dysfunction (ALAT and ASAT activities) or histopathological alterations. Naringin supplementation also significantly improved insulin sensitivity as evaluated by the HOMA index and nutrigenomics revealed that naringin modulated the expression of 1,766 genes. These genes encode proteins involved in different cellular processes, such as lipid metabolism, inflammation and insulin signaling. In conclusion, this study revealed that the hypolipemic and anti-atherogenic effects induced by a nutritional- level naringin supplementation in high-fat high-cholesterol diet could be related to changes in hepatic lipid metabolism and inflammatory response, revealing new in vivo targets of this flavanone.

Transfatty acids are found mainly in processed foods. It has been shown that when their intake is high, total cholesterol, LDL-cholesterol and triacylglycerols are elevated, while HDL-cholesterol decreases. To evaluate a possible effect of these compounds, even in low amounts, C57Bl/6J mice were fed for 7 weeks a diet containing 13·6 % energy as partially hydrogenated rapeseed oil-enriched diet (Trans diet). The Trans diet contained 3 % energy astrans18 : 1 fatty acid (elaidic acid). Control mice were on an isologous diet containing native rapeseed oil (Rapeseed diet) in whichtransfatty acids were undetectable. Total, free and HDL-cholesterol as well as reverse cholesterol transport did not change. However, plasma triacylglycerol and VLDL levels increased. Hepatic gene expression in the Transv.Rapeseed diet were compared using quantitative RT–PCR. The Trans diet produced a 2–3-fold elevation in mRNA of fatty acid synthase and microsomal transfer protein mRNA, explaining (at least in part) the observed increase in triacylglycerols and VLDL. In addition, mice on the Trans diet developed a deficiency in plasma vitamin E accompanied by a higher concentration of F2-isoprostanes, indicative of increased oxidative stress. The 78 kDa glucose-related protein (GRP78) mRNA expression increased 3–4-fold in liver, suggesting that a response against apoptosis was provoked by lipid peroxidation.

To investigate the molecular events controlling reverse cholesterol transport, we compared gene expression of normal mouse liver to that of mice fed a long chain (LC) omega-3 fatty acid-enriched diet. Using cDNA microarrays, we assessed expression levels of 1176 genes, and we found that D-site binding protein (DBP) was three-fold increased in mice on a LC omega-3 fatty acid-rich diet compared to controls. DBP is known to increase transcriptional level of cholesterol 7alpha-hydroxylase (C7alpha), the rate-limiting enzyme for bile acid production and cholesterol excretion, and we found that C7alpha mRNA was also up-regulated by LC omega-3 fatty acids. Moreover, liver X receptor-alpha, another transcription factor up-regulating C7alpha, was three- to four-fold increased in liver of treated mice. On the other hand, we demonstrated that bile acid and cholesterol excretion were two-fold increased. These results show that LC omega-3 fatty acids control cholesterol metabolism in mice at a new endpoint.

In humans, diets rich in fish oil (containing n-3 FA) decrease the incidence of coronary artery diseases. This is thought to be caused by the induction in liver and skeletal muscle of genes involved in lipid oxidation, and to the repression in liver and adipose tissue of genes responsible for lipogenesis. n-3 FA are known to reduce the synthesis of FA and TG in the liver, resulting in a decrease of plasma concentrations of TG-rich lipoproteins. On the other hand, little is known of a possible effect of n-3 FA on HDL metabolism. To investigate this question, female C57Bl/6J mice were fed an n-3 FA-enriched diet for 16 wk. As expected from previous studies, we found that total cholesterol, TG, and phospholipids were reduced in the plasma of treated mice. We also found that HDL-cholesterol decreased after this treatment and that the in vivo fractional catabolic rate of HDL-cholesteryl ester was significantly higher in treated mice than in control mice fed a standard diet. Consistent with these results, treated mice exhibited increased uptake of HDL-cholesteryl ester in the liver. Moreover, quantitative reverse transcriptase-PCR analysis showed a two- to threefold increase in scavenger receptor B-1 gene expression. Taken together, these results suggest that an n-3 FA-enriched diet stimulates one step in the reverse cholesterol transport in mice, probably by increasing the amount of the scavenger receptor class B-1. These effects of n-3 FA on HDL metabolism may contribute to their beneficial effects on the vasculature.