BACKGROUND AND AIMS:Hyperglycerolemia is a rare X-linked inborn error of metabolism whose prevalence is currently unknown. Whether extreme glycerol levels are associated with atherosclerosis is still unknown. The aim of this study was to assess subclinical atherosclerotic cardiovascular disease (ASCVD) in hyperglycerolemia. METHODS:We performed a retrospective analysis in a cohort of patients referred to a tertiary referral center for dyslipidemia between 2000 and 2011. We assessed plasma glycerol levels in all subjects exhibiting hypertriglyceridemia (defined as triglyceride levels > 200 mg/dL). Genetic testing was performed in patients with confirmed hyperglycerolemia. RESULTS:Over 314,268 lipid profiles, 11.8% had hypertriglyceridemia, of whom 13 patients had biological hyperglycerolemia. Genetic tests showed 7 previously undescribed variants of the X-linked glycerol kinase gene. None of the hyperglycerolemic patients presented carotid atherosclerosis at baseline. After a median 11.5 years follow-up, none of the hyperglycerolemic patients developed clinical ASCVD, although noninvasive coronary and carotid imaging revealed the incidence of subclinical atherosclerosis for three of the hyperglycerolemic patients with concomitant classical cardiovascular (CV) risk factors together with an unhealthy trajectory in body weight. CONCLUSIONS:Hyperglycerolemia per se is not associated with premature ASCVD. Its screening should be considered only in patients with persistent hypertriglyceridemia unresponsive to treatment. The confirmation of hyperglycerolemia can help the clinician reassure the patient concerning his CV risk, as no further assessment is required other than common CV risk factors monitoring, including body weight increase and insulin resistance that may appear over the life course.

Journal of Internal MedicineEarly View Research Letter Tuberous xanthomatosis is not necessarily associated with increased plasma concentrations of cholestanol in cerebrotendinous xanthomatosis Jean-Baptiste Bonnet, Jean-Baptiste Bonnet orcid.org/0000-0001-5830-8962 UMR 1302, Desbrest Institute of Epidemiology and Public Health, University of Montpellier, INSERM, CHU, Montpellier, France Endocrinology-Diabetes-Nutrition Department, CHU Montpellier, University of Montpellier, Montpellier, FranceSearch for more papers by this authorPhilippe Couvert, Philippe Couvert APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Endocrine and Oncologic Biochemistry, Paris, France National Institute for Health and Medical Research (INSERM) UMR_S 1166, Faculty of Medicine Pitie-Salpêtriere, Paris, France Sorbonne University, Paris, FranceSearch for more papers by this authorMathilde Di-filippo, Mathilde Di-filippo Dyslipidemia, Nutritional and Digestive Dysfunctions Unit, Department of Biochemistry and Molecular Biology, Biology and Pathology Center - East, Hospices Civils de Lyon, Bron, France CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Claude Bernard Lyon 1 University, Bron, FranceSearch for more papers by this authorFlorian Boissiere, Florian Boissiere Department of Plastic, Reconstructive and Aesthetic Surgery, Burns and Wound Healing Unit, CHRU Lapeyronie, Montpellier, FranceSearch for more papers by this authorJean-Paul Cristol, Jean-Paul Cristol PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, M, ontpellier, France Department of Biochemistry, Hôpital Lapeyronie, CHU Montpellier, Montpellier, FranceSearch for more papers by this authorThibault Sutra, Thibault Sutra Department of Biochemistry, Hôpital Lapeyronie, CHU Montpellier, Montpellier, FranceSearch for more papers by this authorDavid Cheillan, David Cheillan CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Claude Bernard Lyon 1 University, Bron, France Inborn Errors of Metabolism Unit, Department of Biochemistry and Molecular Biology, Biology and Pathology Center - East, Hospices Civils de Lyon, Bron, FranceSearch for more papers by this authorPhilippe Moulin, Philippe Moulin CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Claude Bernard Lyon 1 University, Bron, France Department of Endocrinology, Nutrition and Metabolic Diseases, Hospices Civils de Lyon, Louis Pradel Cardiovascular Hospital, Bron, FranceSearch for more papers by this authorAriane Sultan, Corresponding Author Ariane Sultan a-sultan@chu-montpellier.fr Endocrinology-Diabetes-Nutrition Department, CHU Montpellier, University of Montpellier, Montpellier, France PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, M, ontpellier, France Correspondence: Ariane Sultan, Département Nutrition Endocrinologie Diabète, Hôpital Lapeyronie, 191 avenue du doyen Gaston Giraud, 34295 Montpellier, France. Email: a-sultan@chu-montpellier.frSearch for more papers by this author Jean-Baptiste Bonnet, Jean-Baptiste Bonnet orcid.org/0000-0001-5830-8962 UMR 1302, Desbrest Institute of Epidemiology and Public Health, University of Montpellier, INSERM, CHU, Montpellier, France Endocrinology-Diabetes-Nutrition Department, CHU Montpellier, University of Montpellier, Montpellier, FranceSearch for more papers by this authorPhilippe Couvert, Philippe Couvert APHP, Sorbonne University, Pitié-Salpêtrière Hospital, Endocrine and Oncologic Biochemistry, Paris, France National Institute for Health and Medical Research (INSERM) UMR_S 1166, Faculty of Medicine Pitie-Salpêtriere, Paris, France Sorbonne University, Paris, FranceSearch for more papers by this authorMathilde Di-filippo, Mathilde Di-filippo Dyslipidemia, Nutritional and Digestive Dysfunctions Unit, Department of Biochemistry and Molecular Biology, Biology and Pathology Center - East, Hospices Civils de Lyon, Bron, France CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Claude Bernard Lyon 1 University, Bron, FranceSearch for more papers by this authorFlorian Boissiere, Florian Boissiere Department of Plastic, Reconstructive and Aesthetic Surgery, Burns and Wound Healing Unit, CHRU Lapeyronie, Montpellier, FranceSearch for more papers by this authorJean-Paul Cristol, Jean-Paul Cristol PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, M, ontpellier, France Department of Biochemistry, Hôpital Lapeyronie, CHU Montpellier, Montpellier, FranceSearch for more papers by this authorThibault Sutra, Thibault Sutra Department of Biochemistry, Hôpital Lapeyronie, CHU Montpellier, Montpellier, FranceSearch for more papers by this authorDavid Cheillan, David Cheillan CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Claude Bernard Lyon 1 University, Bron, France Inborn Errors of Metabolism Unit, Department of Biochemistry and Molecular Biology, Biology and Pathology Center - East, Hospices Civils de Lyon, Bron, FranceSearch for more papers by this authorPhilippe Moulin, Philippe Moulin CarMeN Laboratory, UMR INSERM U1060/INRA U1397, Claude Bernard Lyon 1 University, Bron, France Department of Endocrinology, Nutrition and Metabolic Diseases, Hospices Civils de Lyon, Louis Pradel Cardiovascular Hospital, Bron, FranceSearch for more papers by this authorAriane Sultan, Corresponding Author Ariane Sultan a-sultan@chu-montpellier.fr Endocrinology-Diabetes-Nutrition Department, CHU Montpellier, University of Montpellier, Montpellier, France PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, M, ontpellier, France Correspondence: Ariane Sultan, Département Nutrition Endocrinologie Diabète, Hôpital Lapeyronie, 191 avenue du doyen Gaston Giraud, 34295 Montpellier, France. Email: a-sultan@chu-montpellier.frSearch for more papers by this author First published: 09 September 2022 https://doi.org/10.1111/joim.13568Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Conflict of interest The authors declare no conflict of interest. Supporting Information Filename Description joim13568-sup-0001-SuppMat.docx19.4 KB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.

Background and aims: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a wellestablished cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. Methods and results: When TGRL was labelled with fluorescent phospholipid 1,1?-dioctadecyl-3,3,3?,3?-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. Conclusions: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.

Identification of patients with monogenic familial hypercholesterolemia (FH) is demonstrated to be crucial for adapting cardiovascular (CV) risk prevention. Screening strategies for FH have long been based on clinical-biological criteria such as Dutch Lipid Clinic Network Criteria (DLCNC). With the advent of new sequencing technologies (NGS), molecular diagnosis is routinely performed and may be combined with methods aimed to identify polygenic forms that are suggested to have a lower CV risk. In addition, according to DLCNC, untreated LDL-C (uLDL-c) levels above 190 mg/dL are said to be suspicious of FH but overlap also with polygenic forms. Gathering several years of molecular analysis (monogenic and polygenic), we propose a readjustment of criteria for screening and diagnosis of FH in France notably based on a combined biochemical and molecular score. Since 2015, 3736 index cases with “possible FH” (DLCNC) were analysed by NGS (LDLR, PCSK9, ApoB and ApoE genes) as well as for 12 SNPs combined in a polygenic score (GS12). We further selected 2743 subjects over 18 years old with uLDL-c above 190 mg/dL in order to analyse the prevalence of monogenic FH by deciles of uLDL-C as well as GS12 distribution. In our study group of 2743 subjects, 1222 cases (so-called “mutated”) had a mutation (null or missense), 158 had a variant of unknown significance and 1363 (so-called “non-mutated”) had no molecular defect. In this cohort of severe hypercholesterolemia, mutated patients represented only 17% of subjects within the lower uLDL-c decile (LDLc < 206 mg/dL), whereas they accounted for 88% of the upper decile (LDLc > 365 mg/dL). The uLDL-c cut-off associated with a significantly higher prevalence of monogenic FH was 293 mg/dL, corresponding to the 8th uLDL-c decile (71% of mutated subjects). When we analysed GS12 distribution, we observed a higher prevalence of non-mutated (polygenic) subjects starting from 52% in the 6th GS12-decile and increasing progressively up to the 68% in the higher GS12-decile. Combining uLDL-c and GS12 in a single biochemical and molecular score leads to a higher discrimination power (AUC 0.812) compared to the separate uLDL-c and GS12 scores. A high likelikood of monogenic FH is observed starting from uLDL-c of 290 mg/dL. These findings highlight the importance of family history of hypercholesterolemia (rather than ASCVD) in the screening of FH. The improvement of FH diagnosis by this combined score should allow to better define the CV risk and therapeutic management, once validated in replication cohorts.

A 42-year-old man with no relevant past medical history presented with intermittent mild icterus and no signs of chronic liver disease. Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile. Abdominal ultrasound was unremarkable. A panel of chronic liver diseases was negative except for increased serum (147.4 μg/dL) and urinary (179 μg/24 h) copper, with normal ceruloplasmin. No other Leipzig criteria for Wilson’s disease were found, including a negative test for ATP7B gene mutations (by exome sequencing). Total urinary coproporphyrin was normal with predominance of isomer I (86% of total urinary coproporphyrin output). Clinical and laboratorial profile was compatible with Dubin-Johnson syndrome; however, exome sequencing and search for deletions in the ABBC2 gene (encoding MRP2) only found a heterozygous potentially pathogenic variant (c.1483A>G – p.Lys495Glu). Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4–16 of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis. Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia, caused by the absence of the hepatic function OATP1B1/B3 (leading to impaired hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to impaired hepatic bilirubin excretion), respectively. We report a case of compound hereditary hyperbilirubinemia with a misleading presentation with special focus on its diagnosis, particularly the advantage of extensive unbiased genetic testing by dedicated laboratories. With this case, we aim to highlight the necessity of establishing a diagnosis, reassuring the patient, and avoiding unnecessary invasive and costly diagnostic procedures.

In response to physical exercise and diet, skeletal muscle adapts to energetic demands through large transcriptional changes. This remodelling is associated with changes in skeletal muscle DNA methylation which may participate in the metabolic adaptation to extracellular stimuli. Yet, the mechanisms by which muscle-borne DNA methylation machinery responds to diet and exercise and impacts muscle function are unknown. Here, we investigated the function of de novo DNA methylation in fully differentiated skeletal muscle. We generated muscle-specific DNA methyltransferase 3A (DNMT3A) knockout mice (mD3AKO) and investigated the impact of DNMT3A ablation on skeletal muscle DNA methylation, exercise capacity and energy metabolism. Loss of DNMT3A reduced DNA methylation in skeletal muscle over multiple genomic contexts and altered the transcription of genes known to be influenced by DNA methylation, but did not affect exercise capacity and whole-body energy metabolism compared to wild type mice. Loss of DNMT3A did not alter skeletal muscle mitochondrial function or the transcriptional response to exercise however did influence the expression of genes involved in muscle development. These data suggest that DNMT3A does not have a large role in the function of mature skeletal muscle although a role in muscle development and differentiation is likely.

BackgroundLow concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk.MethodsTo assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase.ResultsWhen the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (−45%) and type 2 diabetes (–25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (−20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [3H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis.ConclusionsFree cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.

Nephrotic range proteinuria has been reported during the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). However, the pathological mechanisms underlying this manifestation are unknown. In this article, we present two cases of collapsing glomerulopathy (CG) associated with acute tubular necrosis during the course of COVID-19, and review the literature for similar reports. In our two cases, as in the 14 cases reported so far, the patients were of African ancestry. The 14 patients assessed had an APOL1 high-risk genotype. At the end of the reported period, two patients had died and five patients were still requiring dialysis. The 16 cases detailed in the present report strongly argue in favour of a causal link between SARS-CoV-2 infection and the occurrence of CG in patients homozygous for APOL1 high-risk genotype for which the term COVID-associated nephropathy (COVIDAN) can be put forward.

Background and Aims: Low concentrations of HDL-cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship with CVD. Mechanisms underlying this association are unknown.

Background and Aims: Severe hypertriglyceridemia above 10 mmol/L increases the pancreatitis risk. Patients were currently diagnosed by 1) the presence of chylomicrons, (2) the post-heparin lipase activity (PHLA) test combined with lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity determination, (3) the genetic study (investigation of mutations on 5 genes: APOA5, LPL, LMF1, APOC2, CPIHBO1), (4) and the fat dependency test. These explorations sometimes give divergent results that cannot easily lead to manage a proper diet based treatment.

BACKGROUND:The Middle East region is characterized by low levels of high-density lipoprotein cholesterol (HDL-C). To date, no genetic study has investigated the cause of low HDL-C in the Lebanese population. OBJECTIVE:Our objective was to study the genetic causes for hypoalphalipoproteinemia in a Lebanese family with extremely low HDL-C levels. METHODS:We sequenced the ABCA1 gene and evaluated cholesterol efflux, inflammatory, and metabolic profiles in the proband and his family. RESULTS:We identified the first Lebanese pathogenic variant in ABCA1 gene causing Tangier disease in a consanguineous family. The proband carried a novel homozygous pathogenic variant p.Gly592Asp in exon 14 of ABCA1, which segregated with the disease in the family. Functional study of the p.Gly592Asp pathogenic variant revealed that lipid-free apolipoprotein A-I-dependent cholesterol efflux was completely abolished in cholesterol-loaded human monocytes-derived macrophages isolated from the proband when compared to controls. Systemic inflammatory and metabolic assessments showed that plasma cytokines (MCP-1, MIP-1α, IL-6, CRP, TNF-α), adhesion molecules (ICAM-1, VCAM-1, E-selectin), inflammatory soluble receptors (sIL-6r, sTNFRI, sTNFRII), and metabolic markers (Insulin, C-peptide) were elevated in the proband when compared to controls. Noninvasive cardiovascular investigation revealed the presence of premature artery lesions in the proband. CONCLUSIONS:It is the first case of Tangier disease reported in Lebanon harboring a novel pathogenic variant in ABCA1. Further genetic research is needed in the Middle East where the consanguinity rate is elevated, to understand the cause of the highly prevalent dyslipidemia. This will help guiding the early diagnosis, management, and prevention of cardiovascular complications.

Objective: Plasma high-density lipoprotein cholesterol (HDL-C) level is a strong inverse predictor of cardiovascular disease (CVD) development. Tangier disease, a consequence of mutations in the ATP binding cassette transporter 1 (ABCA1) gene, is associated with very low HDL-C levels. Still, the relationship between Tangier disease and CVD is not always evident. The study investigates usefulness of lipoprotein subfractions, oxidative stress and paraoxonase 1 (PON1) status assessment for evaluation and management of patient with low HDL-C phenotype. Patient and methods: A 12-year-old boy was hospitalised due to hypertension. Laboratory evaluation revealed low HDL-C level, and subsequent molecular diagnostic confirmed Tangier disease. Lipoprotein subfractions were assessed by gradient-gel electrophoresis. Oxidative stress status was estimated by measuring total antioxidative status, total oxidative status, prooxidative-antioxidative balance, malondialdehyde and advanced oxidation protein products levels. Activity of paraoxonase 1 in serum and its distribution within HDL subclasses was also determined (ten healthy boys aged 13.1 +/- 3.4 years served as the reference group). Results: Analysis of oxidative stress status biomarkers revealed a state of prolonged prooxidants activity. In turn, serum PON1 activity was substantially reduced. The majority of PON1 activity was present on HDL 2 particles. Conclusion: Impaired antioxidative potential of HDL may point toward hidden cardiovascular risk in isolated low HDL-phenotype.

Aim: Cascade screening of Familial Hypercholesterolemia (FH) using genetic testing has been recommended but polygenic origin could reduce the efficiency of such approach. A polyGenic Score (GS) has been described helping to identify polygenic form of FH. We have developed a genetic test combining detection of monogenic form as well as polygenic contribution in FH.

Cerebrotendinous xanthomatosis (CTX) is among the few inherited neurometabolic disorders amenable to specific treatment. It is easily diagnosed using plasma cholestanol. We wished to delineate the natural history of the most common neurological and non-neurological symptoms in thirteen patients with CTX. Diarrhea almost always developed within the first year of life. Cataract and school difficulties usually occurred between 5 and 15 years of age preceding by years the onset of motor or psychiatric symptoms. The median age at diagnosis was 24.5 years old. It appears critical to raise awareness about CTX among paediatricians in order to initiate treatment before irreversible damage occurs.

The role of ATP-binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1-deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1.Summary Background The ATP-binding cassette transporter ABCA1 is required for the conversion of apolipoprotein A-1 to high-density lipoprotein (HDL), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA1 in platelet functions remains poorly characterized.Objective To determine the role of ABCA1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition.Methods and results We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA1-deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium-induced phosphatidylserine exposure. Interestingly, ABCA1-deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 (TXA2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA2, was primarily dependent on external environment and not on the hematopoietic ABCA1. Decreased aggregation and production of TXA2 and eicosanoids were also observed in platelets from Tangier patients.Conclusions Absence of ABCA1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA2 production through a hematopoietic ABCA1-independent mechanism.