230: Heightened risk of coronary atheroma conferred by a decrease in the plasma concentrations of lithocholic acid

ContextThe bile acids receptors Farsenoid X and TGR5 protect against the formation of atheroma in mice, though no evidence have linked coronary atheroma and bile acid in human. Bile acids links these receptors with more or less efficient activation, depending on the species.ObjectiveTo test the hypothesis that changes in concentrations of circulating bile acid species influence the risk of developing coronary atheromas in humans.MethodsPilot, prospective, observational study conducted between June and September 2010. The serum concentrations of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids were measured in a fasting blood sample. Consecutive hospitalized or ambulatory patients undergoing emergency or elective coronary angiograms were eligible for inclusion. Post-cardiac arrest and non-fasting states, hepatic disease, and treatment with antimicrobials, corticosteroids, statins or fibrates were exclusion criteria. Of 393 screened patients, 44 met the study entry criteria, and were divided between 27 patients with (Group A) and 17 without (Group B) angiographically visible coronary atheromas. The pool of circulating bile acids was analyzed to measure the plasmatic concentrations of 28 different bile acid species. The variables associated with the presence of angiographically visible coronary atheromas were examined by single and multiple variable logistic regression analysis.ResultsThe serum lithocholic acid concentration was significantly lower in group A than in group B. By multiple variable analysis, lithocholic acid was the only predictor of coronary atheroma independently of patient gender (odds ratio 2.41 per 0.05 decrease; 95% confidence interval 1.11 to 5.25, P=0.027ConclusionA low serum concentration of lithocholic acid was an independent predictor of coronary atheroma in human

Membrane Lipids in Ultra-High-Risk Patients: Potential Predictive Biomarkers of Conversion to Psychosis

Alterations in membrane lipids are reported in schizophrenia. However, no conclusion can be drawn regarding the extended and predictive value of these alterations in persons at ultra-high risk of psychosis (UHR). Recent studies suggested that sterols’ impact on psychiatric disorders was underestimated. Here, we simultaneously explored sterols, fatty acids (FA), and phospholipids (PL) in UHR persons for the first time. We analysed erythrocyte membrane lipids in 61 UHR persons, including 29 who later converted to psychosis (UHR-C) and 32 who did not (UHC-NC). We used gas chromatography for FA and liquid chromatography tandem with mass spectrometry for sterols and phospholipids. Among UHR individuals, elevated baseline membrane linoleic acid level was associated with conversion to psychosis (26.1% vs. 60.5%, p = 0.02). Combining sterols, FA, and PL membrane composition improved the prediction of psychosis onset (AUC = 0.73). This is the first report showing that membrane sterol participates, with other membrane lipids, in modulating the risk of psychosis. It suggests that membrane lipids could be used as biomarkers for personalised medicine in UHR patients

Crosstalk between the hepatologist and the cardiologist: a future place for the lithocholic acid as a coronary atheroma risk factor?

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Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy

International audienceBesides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes, is unclear. We show that the isolated adipocyte fraction, but not the total undigested adipose tissue (ATs), from obese patients has decreased LAL expression compared with that from nonobese people. Lentiviral-mediated LAL knockdown in the 3T3L1 mouse cell line to mimic the obese adipocytes condition did not affect lysosome density or autophagic flux, but it did increase triglyceride storage and disrupt endoplasmic reticulum cholesterol, as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than did control mice fed a high-fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol level in the former was lower than that of control mice, although triglyceridemia in the two groups of mice was similar. The adipose-specific LAL-overexpressing mouse phenotype depends on the housing temperature and develops only under mild hypothermic stress (e.g., room temperature) but not at thermoneutrality (30°C), demonstrating the prominent contribution of brown AT (BAT) thermogenesis. LAL overexpression increased levels of BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue-cholesterol homeostasis and affects BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure

Combining metabolomics and machine learning models as a tool to distinguish non-classic 21-hydroxylase deficiency from polycystic ovary syndrome without adrenocorticotropic hormone testing

International audienceAbstract STUDY QUESTION Can a combination of metabolomic signature and machine learning (ML) models distinguish nonclassic 21-hydroxylase deficiency (NC21OHD) from polycystic ovary syndrome (PCOS) without adrenocorticotrophic hormone (ACTH) testing? SUMMARY ANSWER A single sampling methodology may be an alternative to the dynamic ACTH test in order to exclude the diagnosis of NC21OHD in the presence of a clinical hyperandrogenic presentation at any time of the menstrual cycle. WHAT IS KNOWN ALREADY The clinical presentation of patients with NC21OHD is similar with that for other disorders of androgen excess. Currently, cosyntropin stimulation remains the gold standard diagnosis of NC21OHD. STUDY DESIGN, SIZE, DURATION The study was designed using a bicentric recruitment: an internal training set included 19 women with NC21OHD and 19 controls used for developing the model; a test set included 17 NC21OHD, 72 controls and 266 PCOS patients used to evaluate the performance of the diagnostic strategy thanks to an ML approach. PARTICIPANTS/MATERIALS, SETTING, METHODS Fifteen steroid species were measured in serum by liquid chromatography–mass spectrometry (LC-MS/MS). This set of 15 steroids (defined as ‘steroidome’) used to map the steroid biosynthesis pathway was the input for our models. MAIN RESULTS AND THE ROLE OF CHANCE From a single sample, modeling involving metabolic pathway mapping by profiling 15 circulating steroids allowed us to identify perfectly NC21OHD from a confounding PCOS population. The constructed model using baseline LC-MS/MS-acquired steroid fingerprinting successfully excluded all 17 NC21OHDs (sensitivity and specificity of 100%) from 266 PCOS from an external testing cohort of originally 549 women, without the use of ACTH testing. Blood sampling timing during the menstrual cycle phase did not impact the efficiency of our model. LIMITATIONS, REASONS FOR CAUTION The main limitations were the use of a restricted and fully prospective cohort as well as an analytical issue, as not all laboratories are equipped with mass spectrometers able to routinely measure this panel of 15 steroids. Moreover, the robustness of our model needs to be established with a larger prospective study for definitive validation in clinical practice. WIDER IMPLICATIONS OF THE FINDINGS This tool makes it possible to propose a new semiology for the management of hyperandrogenism. The model presents better diagnostic performances compared to the current reference strategy. The management of patients may be facilitated by limiting the use of ACTH tests. Finally, the modeling process allows a classification of steroid contributions to rationalize the biomarker approach and highlight some underlying pathophysiological mechanisms. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by ‘Agence Française de Lutte contre le dopage’ and DIM Région Ile de France. This study was supported by the French institutional PHRC 2010-AOR10032 funding source and APHP. All authors declare no competing financial interests. TRIAL REGISTRATION NUMBER N/A

The Goto-Kakizaki rat is a spontaneous prototypical rodent model of polycystic ovary syndrome

International audiencePolycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment

Identification of Bronchoalveolar and Blood Immune-Inflammatory Biomarker Signature Associated with Poor 28-Day Outcome in Critically Ill COVID-19 Patients

Abstract The local immune-inflammatory response elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still poorly described, as well as the extent to which its characteristics may be associated with the outcome of critical Coronavirus disease 2019 (COVID-19). In this prospective monocenter study, all consecutive COVID-19 critically ill patients admitted from February to December 2020 and explored by fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) were included. Biological assays, including digital ELISA cytokine profiling and targeted eicosanoid metabolomic analysis, were performed on paired blood and BAL fluid (BALF). Clinical outcome was assessed through the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) at the 28th day (D28) following the admission to intensive care unit. A D28-WHO-CPS value higher than 5 defined a poor outcome. Seventy-six patients were included, 45 (59%) had a poor day-28 outcome. As compared to their counterparts, patients with D28-WHO-CPS\,>\,5 exhibited a neutrophil-predominant bronchoalveolar phenotype, with a higher BALF neutrophil/lymphocyte ratio, a blunted local type I interferon response, a decompartimentalized immune-inflammatory response illustrated by lower BALF/blood ratio of concentrations of IL-6 (1.68 [0.30\textendash 4.41] vs. 9.53 [2.56\textendash 19.1]; p\,=\,0.001), IL-10, IL-5, IL-22 and IFN-γ, and a biological profile of vascular endothelial injury illustrated by a higher blood concentration of VEGF and higher blood and/or BALF concentrations of several vasoactive eicosanoids. In critically ill COVID-19 patients, we identified bronchoalveolar and blood immune-inflammatory biomarker signature associated with poor 28-day outcome