Biology subjects

Cariou, B.

Publications and source records attributed to Cariou, B..

9 recordsLinked to original sources

bioRxiv2026

LIPC-E97G Gain-of-function variant potentiates the hypocholesterolemic and anti-atherogenic effects of evinacumab in Ldlr-/- mice

Introduction: Cardiovascular disease is the leading cause of death worldwide (Dagenais et al. 2020), and its main risk factor is LDL-C (Hagenbeek et al. 2020). Only a few genes are associated with LDL-C concentrations, and only 2 genes, ANGPTL3 (Musunuru et al. 2010) and LIPC, are associated with familial combined hypocholesterolemia. Our team recently identified the second genetic cause associated with familial combined hypocholesterolemia, a gain-of-function mutant of the LIPC gene encoding hepatic lipase (HL), LIPC-E97G (Dijk et al. 2022). Although the mode of action of this variant remains largely unknown, we have demonstrated that it significantly increases the phospholipase activity of HL and affects lipoprotein metabolism by promoting plasma cholesterol clearance, particularly of LDL and HDL. Objective: The aim of this study was to explore the additive effect of our HL-E97G variant with a pharmacological inhibitor of the ANGPTL3 protein, evinacumab, on cholesterolemia and atherosclerosis. Materiel and methods: Atherosclerosis measurements were performed on Ldlr-/- mice fed a pro-atherogenic diet. These mice received a single injection of a liver-targeting AAV8 expressing the wild-type or E97G human form of the LIPC gene (1.10E11 genome copies/mouse) and a weekly injection of NaCl or evinacumab (25 mg/kg/week). Results: From a therapeutic approach, we demonstrated a cumulative effect of HL-E97G with evinacumab. Atherosclerotic lesions in the aortic arch of Ldlr-/- mice were reduced by 36% (p=0.4897) with evinacumab, by 65% (p-value=0.0028) with HL-E97G, and by 80% (p-value < 0.0001) with the combined therapy. Conclusion: Our data demonstrate that HL-E97G reduces the development of atherosclerosis in mice in an LDLR- and ANGPTL3-independent manner, strongly reinforcing the therapeutic potential of HL-E97G for patients at high risk of cardiovascular disease.

physiology↗

bioRxiv2025

Comparative Transcriptomic Analysis of Obesity and Lipodystrophy Reveals Shared Mechanisms and Novel Targets in Adipose Tissue Dysfunction

The global rise in obesity poses a major public health challenge. While chronic energy surplus is a well-established driver of weight gain and obesity, the mechanisms linking adipose tissue (AT) expansion to cardiometabolic complications remain incompletely understood. In obese individuals, dysfunctional AT loses its capacity to store excess lipids, leading to ectopic fat accumulation and contributing to cardiometabolic complications such as type 2 diabetes. However, the molecular events that drive the transition from healthy to dysfunctional adipocytes are poorly defined. At the opposite end of the adiposity spectrum, lipodystrophies represent a heterogeneous group of disorders characterized by selective loss of AT, often accompanied by severe metabolic disturbances. Despite these contrasting adipose phenotypes, both obesity and lipodystrophy result in similar metabolic complications. In this study, we investigated whether AT in these two contrasting conditions shares a common molecular signature. We performed an unbiased comparative transcriptomic analysis of AT from lipodystrophic BSCL2-deficient and obese mice, identifying a shared signature of 129 genes. Using publicly available datasets, we replicated this signature and refined it to 102 genes whose expression is consistently altered in both obese and lipodystrophic adipose tissue. Correlation network analysis, gene ontology, and literature-based refinement revealed that these genes fall into nine functional categories: lipogenesis, adipocyte differentiation, carbohydrate metabolism, mitochondrial function, amino acid metabolism, reactive oxygen species, metabolic processes, immune response, and a group with no clear functional association. Most of these genes expression levels correlated strongly with insulin sensitivity across lipodystrophic and obese mice, as well as human samples. Finally, 52 genetic loci containing these genes harbor variants associated with type 2 diabetes, including 11 loci where genetic associations directly influence candidate gene expression levels. In conclusion, our findings demonstrate that a shared "energetic collapse" of adipocytes, characterized by profound metabolic inflexibility in pathways spanning glucose utilization, lipogenesis, and amino acid catabolism, represents a common pathogenic mechanism underlying adipose tissue dysfunction in both obesity and lipodystrophy. This convergent molecular signature underscores the critical role of intrinsic adipocyte metabolic health in systemic energy homeostasis and insulin sensitivity.

physiology↗

bioRxiv2025

Tripartite ER-Mitochondria-Lipid Droplets contact sites control adipocyte metabolic flexibility

Obesity is a major risk factor for cardiometabolic diseases, with adipocyte dysfunction playing a central role. Understanding how lipid storage and mobilization are regulated--and disrupted--in adipocytes is key to addressing obesity-associated complications. The ER-anchored protein Seipin controls lipid droplet (LD) biogenesis and maintenance, and its loss disrupts ER-LD contact sites. In humans, Seipin deficiency causes generalized lipodystrophy, a severe form of adipocyte dysfunction. We previously showed that Seipin also localizes at ER-mitochondria contact sites (MAM), where it regulates calcium exchange and mitochondrial function. Here, we examined whether Seipin targeting to MAM and ER-LD sites overlaps functionally. We analyzed subcutaneous adipose tissue (AT) from inducible Seipin-knockout mice using transmission electron microscopy (TEM) and proximity ligation assays (PLA) to quantify membrane contact sites (MCS) involving the ER, LDs, and mitochondria. In control mice, feeding reduced MAMs while increasing ER-LD and mitochondria-LD contacts, whereas Seipin deficiency abolished this remodeling. Specifically, under lipid loading, MAMs located in proximity to LDs--tripartite contact sites known as MAM-LD--were increased in control but not in Seipin-deficient adipocytes. Fluorescence recovery after photobleaching assays revealed that Seipin depletion impairs triglyceride transfer to LDs, an effect rescued by the MAM-LD-reinforcing synthetic peptide Linker-ER-Mi. Importantly, this rescue was abolished by silencing the mitochondrial calcium uniporter, demonstrating that calcium exchange is critical for triglyceride storage in LDs. We further investigated how MAM-LD remodeling influences adipocyte metabolic flexibility. Using TEM and PLA, we monitored two MAM subtypes: those forming MAM-LD and those engaging cytosolic mitochondria (MAM-CM). During adipogenesis, MAM-LD frequency increased while MAM-CM decreased. Similarly, in mouse AT and 3T3-L1 adipocytes, lipid loading selectively promoted MAM-LD. Notably, this adaptive remodeling of membrane contact sites was blunted in the adipose tissue of diet-induced obese mice. Genetic disruption of MCS in 3T3-L1 adipocytes altered lipid flux, impaired lipolysis, and reduced insulin signaling. Together, our findings identify MAM-LD contacts as key regulators of adipocyte lipid handling and metabolic flexibility, whose disruption may underlie the metabolic inflexibility of obesity.

cell biology↗

bioRxiv2025

Extracellular vesicles carrying surface-anchored adiponectin prevent obesity-related metabolic complications by enhancing insulin sensitivity

Adiponectin (Adpn) is a potent insulin-sensitizing adipokine with therapeutic promise for type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). Its clinical use is limited by challenges in producing stable, bioactive high-molecular weight forms. Adipocyte-derived extracellular vesicles (EVs) naturally carry oligomeric Adpn on their surface, enhancing hormone stability and activity. Here, we engineered EVs displaying membrane-anchored Adpn (EVPP-Adpn) and control EVs lacking Adpn (EVCTL), and evaluated their metabolic effects in high fat diet (HFD)-induced obesity mice. EVPP-Adpn were purified from HEK293T cells stably transfected with a chimeric Adpn fused to a transmembrane domain and a pilot peptide (PP) directing it to EVs; EVCTL were produced from non-transfected cells. HFD-fed male and female mice received intraperitoneal EV injections for six weeks. EVPP-Adpn improved glucose tolerance and insulin sensitivity, promoted adipocyte lipid storage through insulin-regulated lipogenesis and alleviated MASH features (liver steatosis, inflammation and fibrosis). EVPP-Adpn lowered circulating ceramides and reduced FGF21, indicating improved hepatic metabolism, and activated AKT and AMPK pathways in liver and skeletal muscle, consistent with increased adiponectin signaling. These results demonstrate that surface-anchored Adpn EVs restore tissue-specific insulin signaling and improve obesity-related metabolic dysfunctions, highlighting their potential as a novel biotherapeutic strategy for T2D and MASH.

bioengineering↗

bioRxiv2025

KILDA: identifying KIV-2 repeats from kmers

MotivationHigh concentration of lipoprotein(a), a lipoprotein with proatherogenic properties, is an important risk factor for cardiovascular disease. This concentration is mostly genetically determined by a complex interplay between the number of Kringle-IV type 2 repeats and Lipoprotein(a)-affecting variants. Besides lipoprotein(a) plasma concentration, there is an unmet need to identify individuals most at risk based on their LPA genotype. ResultsWe developed KILDA, a Nextflow pipeline, to identify the number of Kringle-IV type 2 repeats and Lp(a)-affecting variants directly from kmers generated from FASTQ files. The pipeline was tested on the 1000 Genomes Project (n=2459) and results were equivalent to DRAGEN-LPA (R2=0.93). In-silico datasets proved the robustness of KILDAs predictions under different scenarios of sequencing coverage and quality. ConclusionKILDA is an open-source and free-to-use pipeline to identify the number of Kringle-IV type 2 repeats and lipoprotein(a)-associated variants. Its results are equivalent to DRAGEN-LPA, offering a free and robust tool for determining the LPA kringle number even when inputting low coverage libraries. AvailabilityKILDA is publicly available at https://github.com/HCL-HUBL/KILDA along with a recipe to build an Apptainer image containing all the required dependencies. Contact: corentin.molitor@chu-lyon.fr Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2024

Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) underlies daily mitochondrial lysine-malonylation and hepatic metabolism

Circadian rhythms are fundamental to maintaining health and are implicated in various diseases. In the liver, daily rhythms are coordinated via the interplay between feeding rhythms and the molecular circadian clock, ensuring metabolic homeostasis. Disruption of feeding rhythms can lead to circadian misalignment, contributing to metabolic disorders, yet the underlying molecular mechanisms remain unclear. Recent evidence suggests that post-translational modifications play a key role in regulating circadian functional output. In this framework, mitochondria serve as a convergence point, integrating rhythms in metabolism, feeding rhythms and the circadian clock. In the present study, we used a multi-omics approach to investigate the role of the Acyl-CoA synthetase 3 (ACSF3) in driving lysine-malonylation and in regulating daily hepatic metabolism. We found that ACSF3 expression and its mediated impact on lysine-malonylation are rhythmic and largely governed by feeding rhythms. While hepatic ACSF3 knockdown did not alter diet-induced metabolic abnormalities, our results demonstrate that ACSF3 plays a role in the diurnal regulation of liver glycogen storage, de novo lipogenesis, and triglyceride synthesis.

physiology↗

bioRxiv2023

PCSK9 inhibition protects mice from food allergy

The Proprotein Convertase Subtilisin Kexin of type 9 (PCSK9) has been identified in 2003 as the third gene involved in familial hypercholesterolemia. PCSK9 binds to the membrane low-density lipoprotein receptor (LDLR) and promotes its cellular internalization and lysosomal degradation. Beyond this canonical role, PCSK9 was recently described to be involved in several immune responses. However, to date, the contribution of PCSK9 in food allergy remains unknown. Here, we showed that Pcsk9 deficiency or pharmacological inhibition of circulating PCSK9 with a specific monoclonal antibody (m-Ab) protected mice against symptoms of gliadin-induced-food allergy, such as increased intestinal transit time and ear oedema. Furthermore, specific PCSK9 inhibition during the elicitation steps of allergic process was sufficient to ensure anti-allergic effects in mice. Interestingly, the protective effect of PCSK9 inhibition against food allergy symptoms was independent of the LDLR as PCSK9 inhibitors remained effective in Ldlr deficient mice. In vitro, we showed that recombinant gain of function PCSK9 (PCSK9 D374Y) increased the percentage of mature bone marrow derived dendritic cells (BMDCs), promoted naive T cell proliferation and potentiated the gliadin induced basophils degranulation. Altogether, our data demonstrate that PCSK9 inhibition is protective against gliadin induced food allergy in a LDLR-independent manner.

physiology↗

bioRxiv2023

The Sterile Insect Technique can efficiently reduce the reproduction of the spotted wing drosophila (Drosophila suzukii) in strawberry

The spotted wing drosophila (SWD) Drosophila suzukii (Diptera: Drosophilidae) is a pest of soft fruit. Since its introduction in Europe in 2008 farmers struggle to protect their crops. The sterile insect technique (SIT) has proven efficient at controlling numerous fruit fly species and could be deployed to control D. suzukii. In recent years, key elements of SIT applied to D. suzukii have become available. However, field- and field-like experiments are scarce. In this experiment, we assayed the efficacy of a high-performance strain at reducing the reproduction of D. suzukii in complex, yet replicated and controlled conditions. Two ratios of sterile to fertile insects (5:1 and 1:1) using bisexual releases were compared to a control treatment with fertile, wild flies only. The presence of sterile individuals at a 5:1 ratio significantly reduced fly reproduction, measured after 5 days, by an approximate threefold factor. However, the proportion of infested fruits in the treated plots remained unaffected. The number of available berries in the cage appeared an unexpected determinant of fly infestation, suggesting undocumented density-dependent processes. The success of this assay opens the door to larger scales experiments, over several generations, and, in the near future, the field-evaluation of the efficacy of the SIT to control D. suzukii.

ecology↗

bioRxiv2021

Lipidomic analysis of adipose-derived extracellular vesicles reveals their potential as lipid mediators of obesity-associated metabolic complications

Adipose extracellular vesicles (AdEV) transport lipids that could participate to the development of obesity-related metabolic dysfunctions. This study aimed to define mice AdEV lipid signature in either healthy or obesity context by a targeted LC-MS/MS approach. Distinct clustering of AdEV and visceral adipose tissue (VAT) lipidomes by principal component analysis reveals specific lipid composition of AdEV compared to source VAT. Comprehensive analysis identifies enrichment of ceramides and phosphatidylglycerols in AdEV compared to VAT in lean conditions. Lipid subspecies commonly enriched in AdEV highlight specific AdEV-lipid sorting. Obesity impacts AdEV lipidome, driving triacylglycerols and sphingomyelins enrichment in obese versus lean conditions. Obese mice AdEV also display elevated phosphatidylglycerols and acid arachidonic subspecies contents highlighting novel biomarkers and/or mediators of metabolic dysfunctions. Our study identifies specific lipid-fingerprints for plasma, VAT and AdEV that are informative of the metabolic status and underline the signaling capacity of lipids transported by AdEV in obesity-associated complications.

physiology↗