For statistical analysis, Principal Component Analysis (PCA) was performed using mixOmics R package for data overview and outlier identification. Group comparisons were made through linear regression analysis, p-values were adjusted using False Discovery Rate (FDR) and corrected for sex (limma R package). Most discriminant features between the two groups were chosen using an adjusted p-value <1x10e-6 and a fold-change (FC) >1.25 or <0.8 threshold. Annotation was done using in-house database (based on exact mass, retention time, and MS/MS scans) and public LIPID MAPS database with further validation using MS/MS analysis for the most discriminant features.
"],"repository":["MetaboLights"],"study_status":["Public"],"ptm_modification":[""],"instrument_platform":["Liquid Chromatography MS - positive - reverse phase"],"chromatography_protocol":["Lipids were eluted on a Zobrax Eclipse plus C18, 2.1 x 100 mm, 1.8 µm (Agilent Technologies Inc.) heated to 40°C with a constant flow rate at 0.45 mL/min with an 83 min gradient of mobile phase A (0.2% formic acid and 10 mM ammonium formate in water) and mobile phase B (0.2% formic acid and 5mM ammonium formate in methanol/acetonitrile/MTBE 55:35:10 (v/v/v)).
"],"publication":["Glucagon-induced PGC-1α4/PPARγ promotes hepatic lipid storage and macrosteatosis in fasting and MASLD. 10.1101/2025.09.09.674670."],"submitter_name":["Matthieu Schoumacher"],"submitter_affiliation":["Institut de Recherche Clinique de Montreal - IRCM"],"organism_part":["blank sample","liver","Quality Control"],"technology_type":["mass spectrometry assay"],"disease":[""],"extraction_protocol":["Lipids were extracted from 30 mg of liver tissue and spiked with six internal standards (PS(12:0/12:0), PC(14:0/14:0), PE(17:0/17:0), PC(19:0/19:0), Cr(d18:1/10:0), and TG(17:0/17:1/17:0)-d5).
"],"organism":["Mus musculus","blank sample","not applicable"],"full_dataset_link":["https://www.ebi.ac.uk/metabolights/MTBLS13087"],"author":["Jennifer Estall. Institut de Recherche Clinique de Montreal - IRCM. Jennifer.Estall@ircm.qc.ca.","Matthieu Schoumacher. Institut de Recherche Clinique de Montreal - IRCM. matthieu.schoumacher@ircm.qc.ca."],"data_transformation_protocol":["Data collection and processing were done using a previously validated in-house pipeline(Forest et al., 2018) including (1) application of a frequency filter of 80% based on a feature’s presence within each condition, (2) data normalization using cyclic loess algorithm (from the limma R package from Bioconductor), (3) imputation of missing values to 90% of the lowest value, and (4) batch correction for manipulator using ComBat. The final dataset consisted of a matrix in which each sample is described by 1778 features.
"],"study_factor":["Sex","PGC-1a4heptg+"],"submitter_email":["matthieu.schoumacher@ircm.qc.ca"],"sample_collection_protocol":["Hepatocyte-specific PGC-1α4 overexpressing male and female mice (PGC-1α4HepTg+)(Leveille et al., 2020) were compared to age- and sex-matched littermate Alb-Cre+ (WTCre+) control mice. For MASLD modeling, mice were fed a high-fat, high-fructose, and cholesterol-rich diet (D17010103i, Research Diets, 20 kcal% protein, 40 kcal% carbohydrates, and 40 kcal% fat, with 2% w/w cholesterol) for 12 weeks, starting at 5 weeks of age. Liver samples were harvested from male and female PGC-1α4HepTg+ and WTCre+ mice (n = 10-12 per group) fed a MASLD-promoting diet, and untargeted lipidomic analyses were performed using validated protocols for lipid extraction and LC-MS analysis, as previously described (Burelle et al., 2024; Forest et al., 2018).
"],"omics_type":["Metabolomics"],"study_design":["peroxisome proliferator-activated receptor gamma coactivator 1-alpha","Lipidomics","Liver Disease","Metabolic Dysfunction-Associated Steatotic Liver Disease"],"curator_keywords":["peroxisome proliferator-activated receptor gamma coactivator 1-alpha","Lipidomics","Liver Disease","Metabolic Dysfunction-Associated Steatotic Liver Disease"],"mass_spectrometry_protocol":["Samples were injected (volume=0.5 µL) into a 1290 Infinity HPLC coupled to a 6550 QTOF equipped with a dual ESI source (Agilent Technologies Inc., Santa Clara, USA) and analyzed in positive mode (scan m/z range = 50 to 1700).
"],"metabolite_name":["PC32:2","GlcCer42:2;O2","PC32:1","PC32:0","PE(18:1_0:0)","SM43:1;O2","TG53:2","TG53:3","IS_PS24:0","TG53:4","TG38:0","SM34:0;O2","TG50:3;TG(16:1_18:2_16:0);TG(18:1_18:2_14:0)","TG49:1;TG(15:0_16:0_18:1)-a","TG49:3;TG(16:1_16:1_17:1)","SM41:1;O2","PE36:1","TG49:2","PC(20:0_0:0)","TG49:3","PS38:5;PS(18:1_20:4)","CoenzymeQ10","PC(22:5_0:0)-c","TG49:1","CAR,Stearoylcarnitine","PE36:2","PE36:4","TG26:0","PC38:7;PC(16:1_22:6)","PC33:2","PC33:1","PE40:6","PCO-32:0","PC40:6;PC(18:1_22:5)","PC(18:0_0:0)-a","PC(18:0_0:0)-b","DG34:0","DG34:1","TG54:3","TG54:4","TG54:5","TG54:6","DG34:2","TG54:7","PC(16:1_0:0)","PI36:3;PI(18:2_18:1)","PC(20:5_0:0)-b","PC(20:5_0:0)-a","IS_PC28:0","PC42:10;PC(22:6_20:4)","TG56:6;TG(16:0_18:1_22:5);TG(16:0_20:3_20:3)","SM38:1;O2","CAR20:1","TG42:0","PS(20:4_0:0)","PC38:1","DG36:1;DG(18:0_18:1)","SM(d18:1/16:0(OH))","PC30:0","Unknown compound","SM40:2;O2","TG51:3","PC38:5","PC38:4","PC38:3","TG36:0","PE40:5;PE(18:0_22:5)","PC38:2","PC38:7","PC38:6","PC(20:4_0:0)-b","GlcCer42:1;O2","PC(20:4_0:0)-a","PE34:2","PC(20:2_0:0)-b","PC(20:2_0:0)-a","PE(20:5_0:0)","PE(20:4_0:0)-a","CAR,Oleoylcarnitine","SM36:1;O2","PE(20:4_0:0)-b","IS_PC38:0","CE18:0","PC(18:2_0:0)-a","PC(18:2_0:0)-b","SM40:1;O2","PC(22:5_0:0)","PE(18:2_0:0)-a","TG48:2;TG(16:1_18:1_14:0);TG(16:1_16:1_16:0)","PE(18:2_0:0)-b","TG52:3","PCO-38:5","PCO-38:6","TG52:5","TG52:6","PE36:5;PE(16:0_20:5)","IS_PE34:0","PC39:6","SM36:2;O2","PC39:5","TG52:1","PC42:7","DG38:2;DG(18:1_20:1)","CE22:6","TG48:4","TG48:5","PC40:6;PC(20:2_20:4)","TG40:0","TG48:3;TG(14:0_16:1_18:2)","PC(O-18:0/0:0)","TG48:0","PI36:4","TG48:1","PC(22:6_0:0)-b","PC(22:6_0:0)-a","PC42:9","PE(22:6_0:0)-a","PC36:3","PC36:2","SM42:1;O2","PC36:1","CE17:1","PE(22:6_0:0)-b","FA,Arachidonic acid","PE(18:0_0:0)","TG54:5;TG(16:0_18:1_20:4)","PC36:6;PC(14:0_22:6)","PC36:5","PC36:4","PC(20:1_0:0)","PE(16:0_0:0)","CAR,Linoleoylcarnitine","GlcCer34:1;O2","PC(14:0_0:0)-b","PC(19:0_0:0)-b","SM39:1;O2","TG45:0","PC(19:0_0:0)-a","CE18:1","PC40:7;PC(20:4_20:3)","CE18:3","FA,Linoleic acid","PC37:2","CE16:1","TG54:6;TG(18:2_16:0_20:4)","TG50:4;TG(16:1_16:1_18:2)","PCO-36:4","TG50:5","TG50:6","PC37:6","PC37:5","PC37:4","PC37:3","TG50:0","TG50:1","TG50:2","PE40:6;PE(18:1_22:5)","TG50:3","PC40:7","CoenzymeQ9","PC40:8","CE20:4","Cer42:1;O2","PC40:4","SM34:2;O2","PC40:5","PC40:6","SM35:1;O2","TG46:0","PC38:6;PC(16:0_22:6)","PC(22:4_0:0)-b","PI38:3","PI38:4","TG52:4;TG(18:2_16:1_18:1)","PC(22:4_0:0)-a","GlcCer41:1;O2","PC(16:0_0:0)-b","PC(16:0_0:0)-a","SM34:1;O2","PC34:1","PC36:5;PC(16:1_20:4)","TG46:2;TG(12:0_16:1_18:1)","PC34:0","TG48:4;TG(14:1_16:1_18:2)","PC34:4","PC34:3","PC34:2","FA,Docosahexaenoic acid","TG44:2;TG(10:0_16:0_18:1)","SM41:2;O2","TG56:7;TG(16:0_18:2_22:5);TG(16:1_20:3_20:4)","PC(15:0_0:0)","PC38:6;PC(18:2_20:4)","TG51:4;TG(16:1_17:1_18:2);TG(18:2_15:0_18:2)","DG34:4;DG(16:2_18:2)","PE(22:5_0:0)","TG44:2;TG(10:0_16:0_18:2)","PE34:1;PE(16:0_18:1)","PS38:6;PS(16:0_22:6)","PE38:4","PE38:5","CAR,Palmitoylcarnitine","PE38:6","PC35:4","PC35:2","PC35:1","TG56:6","PC(18:1_0:0)-c","TG56:7","PC(18:1_0:0)-b","PCO-34:1","TG56:8","PCO-34:2","ST,Cholesterol","PC(18:1_0:0)-a","GlcCer40:1;O2","DG36:2","PE40:6;PE(20:2_20:4)","DG36:3","DG36:0","PC(17:1_0:0)","PC(17:0_0:0)-b","PC(17:0_0:0)-a","SM42:2;O2","TG46:1;TG(16:0_18:1_12:0);TG(16:0_14:0_16:1)","TG44:0"],"additional_accession":[]},"is_claimable":false,"name":"Glucagon-induced PGC-1aplha4/PPARgamma promotes hepatic lipid storage and macrosteatosis in fasting and MASLD","description":"Please update the study abstract/descriptionThe liver plays a central role in regulating the transition between fasting and feeding states, coordinating glycogen breakdown, gluconeogenesis, fatty acid catabolism, and lipid storage. Disruptions in this balance contribute to metabolic disorders, including Metabolic dysfunction Associated Steatotic Liver Disease (MASLD). Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1a) is a key regulator of these processes, and its various isoforms orchestrate hepatic metabolism. Here, we identify a novel biological pathway downstream of glucagon that promotes the hepatic lipid accumulation associated with fasting. Using gain- and loss-of-function in vivo and in vitro models, we found that glucagon induces sustained expression of PGC-1a4 (a short isoform of the PGC-1a coactivator family), promoting lipid uptake and storage in hepatocytes by increasing PPARγ activity. Increased PPARγ/PGC-1a4 promotes hepatic Fsp27/Cidec expression, leading to lipid droplet expansion and triglyceride trapping in liver. Activity of the PPARGC1A alternative promoter and PGC-1a4 expression were higher in livers of patients with MASLD, and PGC-1a4 expression correlated with macrosteatosis. Consistently, persistent expression of hepatic PGC-1a4 in mice fed a western diet promoted macrosteatosis, exacerbated oxidative stress and altered hepatic lipid composition to resemble worsening Metabolic dysfunction Associated Steatohepatitis (MASH) in humans. Our findings demonstrate that glucagon-induced hepatic PGC-1a4/PPARγ activity facilitates efficient uptake and storage of lipids during fasting, but over-activation of this coordinated metabolic pathway leads to lipid accumulation and worsening of steatosis in MASLD.
","dates":{"publication":"2026-06-16","submission":"2025-10-02"},"accession":"MTBLS13087","cross_references":{}}