Biology subjects

Rimbert, A.

Publications and source records attributed to Rimbert, A..

7 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↗

bioRxiv2026

The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion

BackgroundDecreased hepatic removal of low density lipoproteins (LDL) and increased apolipoprotein B (apoB) production cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease (ASCVD). By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit LDL uptake into Huh-7 hepatocarcinoma cells. MethodsThese findings were validated by targeted in vitro experiments as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes. ResultsSilencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and altered cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol (LDL-C). Rare variants of COPA and COPG1 were enriched among patients with LDL-C > 5 mmol/L. Patients and mice carrying other rare immunopathogenic missense variants of COPA and COPG1 did not present with elevated plasma levels of LDL-C, while hepatic knockdown of murine Copg1 increased the concentrations of non-HDL-cholesterol in plasma and triglycerides in the liver. ConclusionsThe COPI coatomer regulates LDLR activity and apoB secretion as well as lipid content of liver cells. Loss of function of some variants of COPI genes are associated with higher LDL-C levels.

cell biology↗

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

Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis

BackgroundCalcific aortic valve stenosis (AS) affects 3% of older adults and lacks medical treatment. The deacetylase Sirtuin 1 (SIRT1) could be involved in many pathways linked to AS progression. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucose-lowering agents, have been shown to reduce cardiovascular events (likely via SIRT1), but their possible benefits in AS are unknown. Our study aims to uncover the role of SIRT1 in AS progression and assess the benefit of SGLT2i to slow down the aortic valve fibro-calcification processes. MethodsRNA-seq data of human aortic valve specimens were collected from ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VIC) were generated by CRISPR/Cas9. Real-time PCR, immunofluorescence, and calcification assays were used to characterized mutant VICs. Conditioned medium experiments were implemented to evaluate SGLT2i effect on cellular cross-talk and calcification. Diabetic patients data from the Lombardy regional healthcare database, treated with sulphonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. Cumulative incidence of hospitalization for non-rheumatic aortic valve disease was assessed by Kaplan-Meier and multivariable Cox proportional hazards models were used to estimate hazard ratios. ResultsRNA-seq showed that SIRT1 could be a master regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular-matrix remodeling and calcification by modulating key transcription factors. Moreover, calcification assays further support this role, revealing an increased calcification in SIRT1 KD VICs and a concomitant decrease in VIC SIRT1 Over when compared to wild type. Then, exploring SGLT2i impact on calcification, we showed that VICs cultured in SGLT2i-treated-endothelial medium exhibited reduced calcification associated with endothelial-increased nitric oxide levels, while SIRT1 inhibition enhanced VIC calcification. The real-world data analysis revealed that SGLT2i-treated group had a lower incidence of hospitalized patients for non-rheumatic aortic valve disease compared to SU-treated group. ConclusionsOur data identify SIRT1 as a key regulator of fibro-calcific processes in AS and suggest that SGLT2i may slow the aortic valve degeneration through SIRT1 modulation. These findings highlight SGLT2i as a promising therapeutic option for AS prevention and care. Clinical PerspectivesO_ST_ABSWhat is new?C_ST_ABSO_LISirtuin 1 (SIRT1) downregulation is linked to the progression of aortic stenosis (AS) pathological processes and plays a crucial role in mitigating oxidative stress, fibrosis, and calcification. C_LIO_LISodium-glucose co-transporter 2 inhibitor (SGLT2i) treatment of valve endothelial cells results in the secretion of protective factors that reduce valve interstitial cell calcification, highlighting the valuable role of endothelial health in preventing valve degeneration. C_LIO_LIReal-world data indicate that the use of SGLT2i is associated with a lower incidence of hospitalization rate for aortic valve disease as compared to sulfonylureas, suggesting a protective effect against AS in diabetic patients. C_LI What are the clinical implications?O_LIThis study highlights the potential of restoring SIRT1 activity as a therapeutic strategy to mitigate pro-calcific and pro-fibrotic processes in AS. C_LIO_LISGLT2i may offer a breakthrough therapeutic option for AS, a condition currently lacking effective pharmacological treatments, providing new hope for slowing disease progression and improving clinical outcomes. C_LI

cell biology↗

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↗

bioRxiv2023

MicroRNA-541-3p alters lipoproteins to reduce atherosclerosis by degrading Znf101 and Casz1 transcription factors

High apoB-containing low-density lipoproteins (LDL) and low apoA1-containing high-density lipoproteins (HDL) are associated with atherosclerosis. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both decreases apoB and increases apoA1 expression by inducing mRNA degradation of two different transcription factors, Znf101 and Casz1. Znf101 enhances apoB expression while Casz1 represses apoA1 expression. The hepatic knockdown of orthologous Zfp961 and Casz1 genes in mice altered plasma lipoproteins and reduced atherosclerosis without causing hepatic lipid accumulation, most likely by lowering hepatic triglyceride production, increasing HDL cholesterol efflux capacity, and reducing lipogenesis. Notably, human genetic variants in the MIR541, ZNF101, and CASZ1 loci are significantly associated with plasma lipids and lipoprotein levels. This study identifies miR-541-3p and Znf101/Casz1 as potential therapeutic agent and targets, respectively, to reduce plasma lipoproteins and atherosclerosis without causing liver steatosis. O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/565110v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@741dd1org.highwire.dtl.DTLVardef@151ad9aorg.highwire.dtl.DTLVardef@15c96a9org.highwire.dtl.DTLVardef@1a73b2d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. A schematic diagram depicting the role of miR-541-3p in the control of plasma lipoproteins and atherosclerosis.Our data show that miR-541-3p downregulates ZNF101 and CASZ1 by enhancing post-transcriptional degradation of mRNAs after interacting with their 3'-UTRs. Furthermore, our data indicate that ZNF101 is an enhancer of APOB, and CASZ1 is a repressor of APOA1. Hepatic knockdown (KD) of Zfp961, an orthologue of ZNF101, reduces plasma apoB-containing lipoproteins, whereas KD of Casz1 increases high density lipoproteins in mice. Furthermore, we show that hepatic KDs of these transcription factors reduces atherosclerosis in mice induced by the expression of mutant PCSK9. C_FIG

physiology↗

bioRxiv2019

A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels.

Robust inference of causal relationships between gene expression and complex traits using Mendelian Randomization (MR) approaches is confounded by pleiotropy and linkage disequilibrium (LD) between gene expression quantitative loci (eQTLs). Here we propose a new MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data. In simulations, MR-link shows false positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other MR methods we tested, even when only one eQTL variant is present. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals and eQTLs summary statistics from whole blood and liver identified 19 genes causally linked to LDL-C. These include the previously functionally validated SORT1 gene, and the PVRL2 gene, located in the APOE locus, for which a causal role in liver was yet unknown. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.

genetics↗