Biology subjects

Le Goff, W.

Publications and source records attributed to Le Goff, W..

3 recordsLinked to original sources

bioRxiv2021

PCSK9 affects expression of key surface proteins in human pancreatic beta cells through intra- and extracellular regulatory circuits

Aims/hypothesisProprotein convertase subtilisin/kexin 9 (PCSK9) is involved in the degradation of LDLR. However, PCSK9 can target other proteins in a cell-type specific manner. While PCSK9 has been detected in pancreatic islets, its expression in insulin-producing pancreatic beta cells is debated. Herein, we studied PCSK9 expression, regulation and function in the human pancreatic beta cell line EndoC-{beta}H1. MethodsWe assessed PCSK9 expression in mouse and human pancreatic islets, and in the pancreatic beta cell line EndoC-{beta}H1. We also studied PCSK9 regulation by cholesterol, lipoproteins, Mevastatin, and by SREBPs transcription factors. To evaluate PCSK9 function in pancreatic beta cells, we performed PCSK9 gain-and loss-of-function experiments in EndoC-{beta}H1 using siPCSK9 or recombinant PCSK9 treatments, respectively. ResultsWe demonstrate that PCSK9 is expressed and secreted by pancreatic beta cells. In EndoC-{beta}H1 cells, PCSK9 expression is regulated by cholesterol and by SREBPs transcription factors. Importantly, PCSK9 knockdown results in multiple transcriptome, proteome and secretome deregulations and impaired insulin secretion. By gain- and loss-of-function experiments, we observed that PCSK9 regulates the expression levels of LDLR and VLDLR through an extracellular mechanism while CD36, PD-L1 and HLA-ABC are regulated through an intracellular mechanism. Conclusions/interpretationCollectively, these results highlight PCSK9 as an important regulator of CD36, PD-L1 and HLA-ABC cell surface expression in pancreatic beta cells. Data availabilityRNA-seq data have been deposited to GEO database with accession number GSE182016. Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the following identifiers: PXD027921, PXD027911 and PXD027913.

cell biology↗

bioRxiv2020

HIGH FAT DIET STIMULATES BETA-OXIDATION, ALTERS ELECTRICAL PROPERTIES AND INDUCES ADIPOGENICITY OF ATRIA IN OBESE MICE

Metabolic disorders such as obesity are risk factors of atrial fibrillation, not only by sharing comorbidities but likely through their direct impact on atria, notably its adipogenicity. Here, we submitted mice that lack cardiac adipose tissue to a high fat diet and first studied the atrial metabolomic and lipidomic phenotypes using liquid chromatography-mass spectrometry. We found an increased consumption of free fatty acid by the beta-oxidation and an accumulation of long-chain lipids in atria of obese mice. Free fatty acid was the main substrate of mitochondrial respiration studied in the saponin-permeabilized atrial muscle. Conducted action potential recorded in atrial trabeculae was short, and ATP-sensitive potassium current was increased in perforated patch-clamp atrial myocytes of obese mice. There was histological and phenotypical evidence for an accumulation of adipose tissue in obese mice atria. Thus, an obesogenic diet transforms the energy metabolism, causes fat accumulation and induces electrical remodeling of atria myocardium. HIGHLIGHTS- Untargeted metabolomic and lipidomic analysis revealed that a high fat diet induces profound transformation of atrial energy metabolism with beta-oxidation activation and long-chain lipid accumulation. - Mitochondria respiration studied in atrial myocardial trabecula preferentially used Palmitoyl-CoA as energy substrate in obese mice. - Atria of obese mice become vulnerable to atrial fibrillation and show short action potential due to the activation of K-ATP dependent potassium current. - Adipocytes and fat molecular markers were detected in atria of obese mice together with an inflammatory profile consistence with a myocardial accumulation of fat.

physiology↗

bioRxiv2020

Multitrait genetic-phenotype associations to connect disease variants and biological mechanisms

BackgroundGenome-wide association studies (GWAS) uncovered a wealth of associations between common variants and human phenotypes. These results, widely shared across the scientific community as summary statistics, fostered a flurry of secondary analysis: heritability and genetic correlation assessment, pleiotropy characterization and multitrait association test. Amongst these secondary analyses, a rising new field is the decomposition of multitrait genetic effects into distinct profiles of pleiotropy. ResultsWe conducted an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link to biological mechanisms. We started by benchmarking multitrait association tests on a large panel of phenotype sets and established the Omnibus test as the most powerful in practice. We detected 322 new associations that were not previously reported by univariate screening. Using independent significant associations, we investigated the breakdown of genetic association into clusters of variants harboring similar multitrait association profile. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how SNPs within clusters can be mapped to biological pathways and disease mechanisms, providing a putative insight for numerous SNPs with unknown biological function. Finally, for the metabolism set, we investigate the link between gene cluster assignment and success of drug targets in random control trials. We report additional uninvestigated drug targets classified by clusters. ConclusionsMultitrait genetic signals can be decomposed into distinct pleiotropy profiles that reveal consistent with pathways databases and random control trials. We propose this method for the mapping of unannotated SNPs to putative pathways.

genetics↗