The adipocyte apolipoprotein M is negatively associated with inflammation.

Obesity is associated with the development of local adipose tissue (AT) and systemic inflammation. Most adipokines are upregulated with obesity and have pro-inflammatory properties. Few are downregulated and possess beneficial anti-inflammatory effects. The apolipoprotein M (APOM) is an adipokine whose expression is low during obesity and associated with a metabolically healthy AT. Here, the role of adipose-derived APOM on obesity-associated AT inflammation was investigated by measuring the expression of pro-inflammatory genes in human and mouse models. In 300 individuals with obesity, AT APOM mRNA level was negatively associated with plasma hs-CRP. The inflammatory profile was assessed in Apom-/- and WT mice fed a normal chow diet (NCD), or a high-fat diet (HFD) to induce AT inflammation. After HFD, mice had a higher inflammatory profile in AT and liver, and a 50% lower Apom gene expression compared with NCD-fed mice. Apom deficiency was associated with a higher inflammatory signature in AT compared with WT mice but not in the liver. Adeno-associated viruses encoding human APOM were used to induce APOM overexpression: in vivo, in WT mice AT prior to HFD; in vitro, in human adipocytes which conditioned media was applied to ThP-1 macrophages. The murine AT overexpressing APOM gene had a reduced inflammatory profile. The macrophages treated with APOM-enriched media from adipocytes exhibited lower IL6 and MCP1 gene expression compared with macrophages treated with control media, independently of S1P. Our study highlights the protective role of adipocyte APOM against obesity-induced AT inflammation.

4-Cholesten-3-one Modified the Lipidome of MDA-MB-231 Cells and Potentiated the Effect of Docetaxel.

BACKGROUND/AIM: Lipids are essential for energy production, signaling, and membrane formation, hence increased lipid metabolism may lead to cancer growth. 4-cholesten-3-one (4Cone), a sterol metabolite, has various biological activities, including the inhibition of cancer growth. This study examined whether 4Cone could change the lipid profile of triple-negative breast cancer cells (MDA-MB-231) and whether in combination with the anti-cancer chemotherapy docetaxel (TXT) could further reduce cancer aggressiveness. MATERIALS AND METHODS: The effect of 4Cone, TXT, or their combination (4Cone/TXT) on migration and proliferation was examined utilizing the wound healing and MTT assays. The expression of the lipogenesis-related enzymes was assessed using RT-qPCR and lipid profile was examined using mass spectrometry. RESULTS: 4Cone and TXT individually reduced cell viability and migration of MDA-MB-231 cancer cells; however, their combination (4Cone/TXT) had a greater impact on both attributes. All treated cells showed markedly decreased levels of the multidrug resistance enzyme PGP as well as the lipogenic enzymes FASN, ACC1, SCD1, HMGCR, and DGAT. Furthermore, lipid fingerprints were markedly different in treated cells compared with the untreated group. 4Cone increased the percentage of sphingomyelin (SM) while it decreased the percentage of ceramide (Cer); 4Cone in conjunction with TXT had the reverse effect. Triglyceride levels were reduced in 4Cone- and 4Cone/TXT-treated cells, but interestingly, they increased in TXT-treated cells. Additionally, treated cancer cells exhibited changes in glycerophospholipid subclasses. CONCLUSION: 4Cone alone or in combination with TXT alters the lipid profile by reducing a key lipogenic enzyme, resulting in the inhibition of cell proliferation and migration.

Metabolic profiling of glioblastoma stem cells reveals pyruvate carboxylase as a critical survival factor and potential therapeutic target.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance. METHODS: We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic, and phenotypic studies. RESULTS: We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models. CONCLUSIONS: Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM.

Identification of circulating apolipoprotein M as a new determinant of insulin sensitivity and relationship with adiponectin.

BACKGROUND: The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. METHODS: Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. RESULTS: Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < -0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < -0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = -0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. CONCLUSIONS: The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. TRIAL REGISTRATION: NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.

Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy improves lipid and glucose homeostasis in ob/ob mice.

OBJECTIVE: The objective of this study was to compare the general and metabolic impact of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) with Roux-en-Y gastric bypass (RYGB) in an obese (ob/ob) mouse model. METHODS: 10-week-old male ob/ob mice underwent either SADI-S, RYGB, or laparotomy surgery (Sham group). General and metabolic parameters were assessed during a 5-week period thereafter. RESULTS: SADI-S induced a deeper weight loss ([mean ± SEM] -41.2% ± 3.3%) than RYGB (-5.6% ± 3.5%, p < 0.001) compared with the Sham group (+6.3% ± 1.0%, p < 0.05). A significant food restriction was observed after SADI-S only (-31%, 117.4 ± 10.3 g vs. 170.2 ± 5.2 g of food at day 35 in Sham group mice, p < 0.001). Random-fed glycemia and glucose tolerance were more improved after SADI-S than RYGB. SADI-S decreased plasma cholesterol concentration by 60% (0.49 ± 0.04 g/L vs. 1.40 ± 0.10 g/L in the Sham group at day 35, p < 0.01), significantly more than RYGB (1.04 ± 0.14 g/L, p = 0.018). Plasma sitosterol/cholesterol and campesterol/cholesterol ratios were decreased after SADI-S, suggesting a reduced intestinal cholesterol absorption. SADI-S increased exogenous plasma cholesterol-D7 clearance and fecal elimination, also indicating an increased plasma cholesterol excretion. Studying a pair-fed group demonstrated that calorie restriction alone did not explain the beneficial impact of SADI-S. CONCLUSIONS: SADI-S is associated with a greater improvement in lipid and glucose homeostasis than RYGB in ob/ob mice.

Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults.

BACKGROUND: Adenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its relationship with physical activity (PA) remains unclear. Additionally, the apolipoprotein A-I (apoA-I), a PA-modulated lipoprotein could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase. We examined here the associations between chronic PA and plasma IF1 concentrations among older adults, and we investigated whether apoA-I mediated these associations. METHODS: In the present work, 1096 healthy adults (63.8% women) aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included. IF1 plasma concentrations (square root of ng/mL) were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial, while PA levels (square root of metabolic equivalent task min/week) were assessed using questionnaires administered each year from baseline to the 3-year visit. Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations. Mediation analyses were conducted to examine whether apoA-I mediated these associations. Mixed-effect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA. RESULTS: Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations (B = 0.021; SE = 0.010; p = 0.043). Mediation analyses revealed that about 37.7% of this relationship was mediated by apoA-I (Bab = 0.008; SE = 0.004; p = 0.023). Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years (time × IF1: B = -0.148; SE = 0.066; p = 0.025). CONCLUSION: This study demonstrated that regular PA is associated with plasma IF1 concentrations, and it suggests that apoA-I partly mediates this association. Additionally, this study found that baseline concentrations of IF1 can predict future changes in PA. However, further research is needed to fully understand the mechanisms underlying these observations.

Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia.

BACKGROUND: The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in dyslipidemia may go beyond its immediate effects on low-density lipoprotein receptor (LDL-R) activity. OBJECTIVE: This study aimed to assess PCSK9-derived alterations of high-density lipoprotein (HDL) physiology, which bear a potential to contribute to cardiovascular risk profile. METHODS: HDL was isolated from 33 patients with familial autosomal dominant hypercholesterolemia (FH), including those carrying PCSK9 gain-of-function (GOF) genetic variants (FH-PCSK9, n = 11), together with two groups of dyslipidemic patients employed as controls and carrying genetic variants in the LDL-R not treated (ntFH-LDLR, n = 11) and treated (tFH-LDLR, n = 11) with statins, and 11 normolipidemic controls. Biological evaluations paralleled by proteomic, lipidomic and glycomic analyses were applied to characterize functional and compositional properties of HDL. RESULTS: Multiple deficiencies in the HDL function were identified in the FH-PCSK9 group relative to dyslipidemic FH-LDLR patients and normolipidemic controls, which involved reduced antioxidative, antiapoptotic, anti-thrombotic and anti-inflammatory activities. By contrast, cellular cholesterol efflux capacity of HDL was unchanged. In addition, multiple alterations of the proteomic, lipidomic and glycomic composition of HDL were found in the FH-PCSK9 group. Remarkably, HDLs from FH-PCSK9 patients were systematically enriched in several lysophospholipids as well as in A2G2S2 (GP13) glycan and apolipoprotein A-IV. Based on network analysis of functional and compositional data, a novel mosaic structure-function model of HDL biology involving FH was developed. CONCLUSION: Several metrics of anti-atherogenic HDL functionality are altered in FH-PCSK9 patients paralleled by distinct compositional alterations. These data provide a first-ever overview of the impact of GOF PCSK9 genetic variants on structure-function relationships in HDL.

Effect of omega-3 fatty acid ethyl esters on postprandial arterial elasticity in patients with familial hypercholesterolemia.

BACKGROUND: Impaired arterial elasticity reflects increased risk of atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH). Treatment with omega-3 fatty acid ethyl esters (ω-3FAEEs) in FH patients has been shown to improve postprandial triglyceride-rich lipoprotein (TRL) metabolism, including TRL-apolipoprotein(a) [TRL-apo(a)]. Whether ω-3FAEE intervention also improves postprandial arterial elasticity in FH has not been demonstrated. METHODS: We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω-3FAEEs (4 g/day) on postprandial arterial elasticity in 20 FH subjects following ingestion of an oral fat load. Fasting and postprandial large (C1) and small (C2) artery elasticity at 4 and 6 h were measured by pulse contour analysis of the radial artery. The area under-the-curves (AUCs) (0-6 h) for C1, C2, plasma triglycerides and TRL-apo(a) were determined using the trapezium rule. RESULTS: Compared with no treatment, ω-3FAEEs significantly increased fasting (+9%, P < 0.05) and postprandial C1 at 4 h (+13%, P < 0.05) and at 6 h (+10%, P < 0.05), with improvement in the postprandial C1 AUC (+10%, P < 0.01). ω-3FAEEs also decreased postprandial triglyceride and TRL-apo(a) AUCs (-17% and -19%, respectively, P < 0.05). ω-3FAEEs had no significant effect on fasting and postprandial C2. The change in C1 AUC was inversely associated with the changes in the AUC of triglycerides (r = -0.609, P < 0.01) and TRL-apo(a) (r = -0.490, P < 0.05). CONCLUSIONS: High-dose ω-3FAEEs improves postprandial large artery elasticity in adults with FH. Reduction in postprandial TRL-apo(a) with ω-3FAEEs may contribute to the improvement in large artery elasticity. However, our findings need to be confirmed in a larger population. CLINICAL TRIAL REGISTRATION: https://www. CLINICALTRIALS: com/NCT01577056.

Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism.

BACKGROUND: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. APPROACH AND RESULTS: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F ( APOF ) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo , and reduced hepatocyte VLDL uptake by ~15% in vitro . Transcriptomic analysis of APOF -overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1 , among others. CONCLUSION: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.

Effect of Omega-3 Fatty Acid Supplementation on the Postprandial Metabolism of Apolipoprotein(a) in Familial Hypercholesterolemia.

AIM: Lipoprotein(a) (Lp(a)) is a low-density lipoprotein-like particle containing apolipoprotein(a) (apo(a)) that increases the risk of atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH). Postprandial redistribution of apo(a) protein from Lp(a) to triglyceride-rich lipoproteins (TRLs) may also increase the atherogenicity of TRL particles. Omega-3 fatty acid (ω3FA) supplementation improves postprandial TRL metabolism in FH subjects. However, its effect on postprandial apo(a) metabolism has yet to be investigated. METHODS: We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω3FA supplementation (4 g/day) on postprandial apo(a) responses in FH patients following ingestion of an oral fat load. Postprandial plasma total and TRL-apo(a) concentrations were measured by liquid chromatography with tandem mass spectrometry, and the corresponding areas under the curve (AUCs) (0-10h) were determined using the trapezium rule. RESULTS: Compared with no ω3FA treatment, ω3FA supplementation significantly lowered the concentrations of postprandial TRL-apo(a) at 0.5 (-17.9%), 1 (-18.7%), 2 (-32.6%), and 3 h (-19.2%) (P＜0.05 for all). Postprandial TRL-apo(a) AUC was significantly reduced with ω3FA by 14.8% (P＜0.05). By contrast, ω3FA had no significant effect on the total AUCs of apo(a), apoC-III, and apoE (P＞0.05 for all). The decrease in postprandial TRL-apo(a) AUC was significantly associated with changes in the AUC of triglycerides (r=0.600; P＜0.01) and apoB-48 (r=0.616; P＜0.01). CONCLUSIONS: Supplementation with ω3FA reduces postprandial TRL-apo(a) response to a fat meal in FH patients; this novel metabolic effect of ω3FA may have implications on decreasing the risk of ASCVD in patients with FH, especially in those with elevated plasma triglyceride and Lp(a) concentrations. However, the clinical implications of these metabolic findings require further evaluation in outcome or surrogate endpoint trials.

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study.

AIM: Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes. METHODS: In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models. RESULTS: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P   = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P  = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P  <  0.0001) and apoA-I (r = 0.33, P  <  0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P   = 0.012). CONCLUSION: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.

UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from early T cell progenitors. Since relapsed T-ALL is associated with a poor prognosis improving initial treatment of patients is essential to avoid resistant selection of T-ALL. During initiation, development, metastasis and even in response to chemotherapy, tumor cells face strong metabolic challenges. In this study, we identify mitochondrial UnCoupling Protein 2 (UCP2) as a tricarboxylic acid (TCA) cycle metabolite transporter controlling glutamine metabolism associated with T-ALL cell proliferation. In T-ALL cell lines, we show that UCP2 expression is controlled by glutamine metabolism and is essential for their proliferation. Our data show that T-ALL cell lines differ in their substrate dependency and their energetic metabolism (glycolysis and oxidative). Thus, while UCP2 silencing decreases cell proliferation in all leukemia cells, it also alters mitochondrial respiration of T-ALL cells relying on glutamine-dependent oxidative metabolism by rewiring their cellular metabolism to glycolysis. In this context, the function of UCP2 in the metabolite export of malate enables appropriate TCA cycle to provide building blocks such as lipids for cell growth and mitochondrial respiration. Therefore, interfering with UCP2 function can be considered as an interesting strategy to decrease metabolic efficiency and proliferation rate of leukemia cells.

Link between Omega 3 Fatty Acids Carried by Lipoproteins and Breast Cancer Severity.

According to the International Agency for Research on Cancer (IARC) more than 10% of cancers can be explained by inadequate diet and excess body weight. Breast cancer is the most common cancer affecting women. The goal of our study is to clarify the relationship between ω3 fatty acids (FA) carried by different lipoproteins and breast cancer (BC) severity, according to two approaches: through clinic-biological data and through in vitro breast cancer cell models. The clinical study has been performed in sera from a cohort of BC women (n = 140, ICO, France) whose tumors differed by their hormone receptors status (HR− for tumors negative for estrogen receptors and progesterone receptors, HR+ for tumors positive for either estrogen receptors or progesterone receptors) and the level of proliferation markers (Ki-67 ≤ 20% Prolif− and Ki-67 ≥ 30% Prolif+). Lipids and ω3FA have been quantified in whole serum and in apoB-containing lipoproteins (Non-HDL) or free of it (HDL). Differences between Prolif− and Prolif+ were compared by Wilcoxon test in each sub-group HR+ and HR−. Results are expressed as median [25th−75th percentile]. Plasma cholesterol, triglycerides, HDL-cholesterol and Non-HDL cholesterol did not differ between Prolif− and Prolif+ sub-groups of HR− and HR+ patients. Plasma EPA and DHA concentrations did not differ either. In the HR− group, the distribution of EPA and DHA between HDL and Non-HDL differed significantly, as assessed by a higher ratio between the FA concentration in Non-HDL and HDL in Prolif− vs. Prolif+ patients (0.20 [0.15−0.36] vs. 0.04 [0.02−0.08], p = 0.0001 for EPA and 0.08 [0.04−0.10] vs. 0.04 [0.01−0.07], p = 0.04 for DHA). In this HR− group, a significant increase in Non-HDL EPA concentration was also observed in Prolif− vs. Prolif+ (0.18 [0.13−0.40] vs. 0.05 [0.02−0.07], p = 0.001). A relative enrichment on Non-HDL in EPA and DHA was also observed in Prolif− patients vs. Prolif+ patients, as assessed by a higher molar ratio between FA and apoB (0.12 [0.09−0.18] vs. 0.02 [0.01−0.05], p < 0.0001 for EPA and 1.00 [0.73−1.69 vs. 0.52 [0.14−1.08], p = 0.04 for DHA). These data were partly confirmed by an in vitro approach of proliferation of isolated lipoproteins containing EPA and DHA on MDA-MB-231 (HR−) and MCF-7 (HR+) cell models. Indeed, among all the studied fractions, only the correlation between the EPA concentration of Non-HDL was confirmed in vitro, although with borderline statistical significance (p = 0.07), in MDA-MB-231 cells. Non-HDL DHA, in the same cells model was significantly correlated to proliferation (p = 0.04). This preliminary study suggests a protective effect on breast cancer proliferation of EPA and DHA carried by apo B-containing lipoproteins (Non-HDL), limited to HR− tumors.

Identification of 8-Hydroxyquinoline Derivatives That Decrease Cystathionine Beta Synthase (CBS) Activity.

CBS encodes a pyridoxal 5'-phosphate-dependent enzyme that catalyses the condensation of homocysteine and serine to form cystathionine. Due to its implication in some cancers and in the cognitive pathophysiology of Down syndrome, the identification of pharmacological inhibitors of this enzyme is urgently required. However, thus far, attempts to identify such molecules have only led to the identification of compounds with low potency and limited selectivity. We consequently developed an original, yeast-based screening method that identified three FDA-approved drugs of the 8-hydroxyquinoline family: clioquinol, chloroxine and nitroxoline. These molecules reduce CBS enzymatic activity in different cellular models, proving that the molecular mechanisms involved in yeast phenotypic rescue are conserved in mammalian cells. A combination of genetic and chemical biology approaches also revealed the importance of copper and zinc intracellular levels in the regulation of CBS enzymatic activity-copper promoting CBS activity and zinc inhibiting its activity. Taken together, these results indicate that our effective screening approach identified three new potent CBS inhibitors and provides new findings for the regulation of CBS activity, which is crucial to develop new therapies for CBS-related human disorders.

Nutritional biomarkers and heart failure requiring hospitalization in patients with type 2 diabetes: the SURDIAGENE cohort.

BACKGROUND: Heart failure (HF) is a growing complication and one of the leading causes of mortality in people living with type 2 diabetes (T2D). Among the possible causes, the excess of red meat and the insufficiency of vegetables consumption are suspected. Such an alimentation is associated with nutritional biomarkers, including trimethylamine N-oxide (TMAO) and its precursors. Here, we aimed to study these biomarkers as potential prognostic factors for HF in patients with T2D. METHODS: We used the SURDIAGENE (SURvival DIAbetes and GENEtics) study, a large, prospective, monocentric cohort study including 1468 patients with T2D between 2001 and 2012. TMAO and its precursors (trimethylamine [TMA], betaine, choline, and carnitine) as well as thio-amino-acids (cysteine, homocysteine and methionine) were measured by liquid chromatography-tandem mass spectrometry. The main outcome was HF requiring Hospitalization (HFrH) defined as the first occurrence of acute HF leading to hospitalization and/or death, established by an adjudication committee, based on hospital records until 31st December 2015. The secondary outcomes were the composite event HFrH and/or cardiovascular death and all-cause death. The association between the biomarkers and the outcomes was studied using cause-specific hazard-models, adjusted for age, sex, history of coronary artery disease, NT-proBNP, CKD-EPI-derived eGFR and the urine albumin/creatinine ratio. Hazard-ratios (HR) are expressed for one standard deviation. RESULTS: The data of interest were available for 1349/1468 of SURDIAGENE participants (91.9%), including 569 (42.2%) women, with a mean age of 64.3 ± 10.7 years and a median follow-up of 7.3 years [25th-75th percentile, 4.7-10.8]. HFrH was reported in 209 patients (15.5%), HFrH and/or cardiovascular death in 341 (25.3%) and all-cause death in 447 (33.1%). In unadjusted hazard-models, carnitine (HR = 1.20, 95% CI [1.05; 1.37]), betaine (HR = 1.34, [1.20; 1.50]), choline (HR = 1.35, [1.20; 1.52]), TMAO (HR = 1.32, [1.16; 1.50]), cysteine (HR = 1.38, [1.21; 1.58]) and homocysteine (HR = 1.28, [1.17; 1.39]) were associated with HFrH, but not TMA and methionine. In the fully adjusted models, none of these associations was significant, neither for HFrH nor for HFrH and/or CV death, when homocysteine only was positively associated with all-cause death (HR = 1.16, [1.06; 1.27]). CONCLUSIONS: TMAO and its precursors do not appear to be substantial prognosis factors for HFrH, beyond usual cardiac- and kidney-related risk factors, whereas homocysteine is an independent risk factor for all-cause death in patients with T2D.

Altered epithelial barrier functions in the colon of patients with spina bifida.

Our objectives were to better characterize the colorectal function of patients with Spina Bifida (SB). Patients with SB and healthy volunteers (HVs) completed prospectively a standardized questionnaire, clinical evaluation, rectal barostat, colonoscopy with biopsies and faecal collection. The data from 36 adults with SB (age: 38.8 [34.1-47.2]) were compared with those of 16 HVs (age: 39.0 [31.0-46.5]). Compared to HVs, rectal compliance was lower in patients with SB (p = 0.01), whereas rectal tone was higher (p = 0.0015). Ex vivo paracellular permeability was increased in patients with SB (p = 0.0008) and inversely correlated with rectal compliance (r = - 0.563, p = 0.002). The expression of key tight junction proteins and inflammatory markers was comparable between SB and HVs, except for an increase in Claudin-1 immunoreactivity (p = 0.04) in SB compared to HVs. TGFß1 and GDNF mRNAs were expressed at higher levels in patients with SB (p = 0.02 and p = 0.008). The levels of acetate, propionate and butyrate in faecal samples were reduced (p = 0.04, p = 0.01, and p = 0.02, respectively). Our findings provide evidence that anorectal and epithelial functions are altered in patients with SB. The alterations in these key functions might represent new therapeutic targets, in particular using microbiota-derived approaches.Clinical Trials: NCT02440984 and NCT03054415.

Late-Stage Glioma Is Associated with Deleterious Alteration of Gut Bacterial Metabolites in Mice.

Brain-gut axis refers to the bidirectional functional connection between the brain and the gut, which sustains vital functions for vertebrates. This connection also underlies the gastrointestinal (GI) comorbidities associated with brain disorders. Using a mouse model of glioma, based on the orthotopic injection of GL261 cell line in syngeneic C57BL6 mice, we show that late-stage glioma is associated with GI functional alteration and with a shift in the level of some bacterial metabolites in the cecum. By performing cecal content transfer experiments, we further show that cancer-associated alteration in cecal metabolites is involved in end-stage disease progression. Antibiotic treatment results in a slight but significant delay in mice death and a shift in the proportion of myeloid cells in the brain tumor environment. This work rationally considers microbiota modulating strategies in the clinical management of patients with late-stage glioma.

Circulating HDL and Non-HDL Associated Apolipoproteins and Breast Cancer Severity.

Plasma lipids are carried within lipoproteins with various apolipoprotein content. This study evaluates the interest of measuring the apolipoproteins of circulating lipoproteins in breast cancer. Patients with early-stage breast cancer (n = 140) were included. Tumors differed by the expression of estrogen and progesterone receptor (HR- and HR+ for negative and positive expression) and the proliferation marker Ki-67 (≤20% or ≥30%). Apolipoprotein concentrations were determined in plasma, HDL and non-HDL fractions, and results are given in mg/dL, median (25th-75th). Patients did not differ in their plasma and lipoprotein lipid concentrations. HDL apoC-I and non-HDL apoC-II were reduced (1.34 (1.02-1.80) vs. 1.61 (1.32-2.04), p = 0.04; 0.31 (0.18-0.65) vs. 0.63 (0.39-1.02), p = 0.01; respectively), in RH-/high Ki-67 patients in comparison to RH-/low Ki-67 patients, while plasma apoD and HDL apoD were higher (3.24 (2.99-4.16) vs. 3.07 (2.39-3.51), p = 0.04; 2.74 (2.36-3.35) vs. 2.45 (2.01-2.99), p = 0.04; respectively). When RH+/high Ki-67 patients were compared with RH+/low Ki-67 patients, HDL apoC-I and HDL apoC-III were higher (1.56 (1.20-1.95) vs. 1.35 (1.10-1.62), p = 0.02; 2.80 (2.42-3.64) vs. 2.38 (1.69-2.96), p = 0.02; respectively). The distribution of exchangeable apolipoproteins, such as apoC-I, apoC-II, apoC-III, apoD, between lipoproteins is linked to the severity of breast cancer.

Effect of Parathyroidectomy on Metabolic Homeostasis in Primary Hyperparathyroidism.

Background: The benefits of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism (PHPT) are controversial. This monocentric, observational, prospective study aimed to assess the effects of parathyroidectomy on glucose and lipid metabolism in classic or mild PHPT. Methods: Patients who underwent parathyroidectomy for classic (calcemia >2.85 mmol/L) or mild PHPT (calcemia ≤2.85 mmol/L) between 2016 and 2019 were included. A metabolic assessment was performed before and 1 year after parathyroidectomy. Patients with a history of diabetes were excluded. Results: Nineteen patients had classic and 120 had mild PHPT. Ninety-five percent were normocalcemic 6 months after surgery. Fasting plasma glucose and insulin levels decreased after parathyroidectomy in patients with mild PHPT (p < 0.001). HOMA-IR decreased after surgery in the overall population (p < 0.001), while plasma adiponectin concentrations increased in patients with both classic (p = 0.005) and mild PHPT (p < 0.001). Plasma triglyceride levels decreased significantly only in patients with classic PHPT (p = 0.021). Plasma PCSK9 levels decreased in patients with mild PHPT (p < 0.001). Conclusions: Parathyroidectomy for PHPT improves insulin resistance and decreases plasma triglyceride levels in classic PHPT and plasma PCSK9 levels in mild PHPT. Further studies are needed to better characterize the consequences of such metabolic risk factors' improvements on cardiovascular events.