Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease
| Autor: | Emile Levy, Nickolas Auclair, Lena Ahmarani, Jean-François Beaulieu, Noël Peretti, Nathalie Patey, Schohraya Spahis, Alain T. Sané |
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| Přispěvatelé: | CarMeN, laboratoire, Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université de Sherbrooke (UdeS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche du CHU Sainte-Justine [Montreal] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
[SDV]Life Sciences [q-bio] CRD Chylomicron retention disease AMPK AMP-Activated protein kinase 030204 cardiovascular system & hematology MTTP Microsomal triglyceride transfer protein medicine.disease_cause Biochemistry pAMPK Phospho AMPK Microsomal triglyceride transfer protein Hypobetalipoproteinemias 0302 clinical medicine Endocrinology lipid metabolism fatty acid β-oxidation Mutation TG triglyceride embryonic lethality CM Chylomicron chylomicron SAR1B [SDV] Life Sciences [q-bio] pACC Phospho ACC dietary fat Lipogenesis CHOL Cholesterol Chylomicron retention disease Research Article medicine.medical_specialty Sar1b chylomicron retention disease QD415-436 Biology CPT1 Carnitine palmitoyl transferase lipogenesis 03 medical and health sciences Malabsorption Syndromes Internal medicine medicine Genetically modified animal CRISPR/Cas9 COPII Coat protein complex II ACADL Acyl-CoA dehydrogenase and long chain ACC Acetyl CoA carboxylase Lipid metabolism Cell Biology medicine.disease gene defects 030104 developmental biology biology.protein Chylomicron |
| Zdroj: | Journal of Lipid Research Journal of Lipid Research, 2021, 62, pp.100085. ⟨10.1016/j.jlr.2021.100085⟩ Journal of Lipid Research, American Society for Biochemistry and Molecular Biology, 2021, 62, pp.100085. ⟨10.1016/j.jlr.2021.100085⟩ Journal of Lipid Research, Vol 62, Iss, Pp 100085-(2021) |
| ISSN: | 0022-2275 |
| Popis: | International audience; Chylomicron retention disease (CRD) is an autosomal recessive disorder associated with biallelic Sar1b mutations leading to defects in intracellular chylomicron (CM) trafficking and secretion. To date, a direct cause-effect relationship between CRD and Sar1b mutation has not been established, but genetically modified animal models provide an opportunity to elucidate unrecognized aspects of these mutations. To examine the physiological role and molecular mechanisms of Sar1b function, we generated mice expressing either a targeted deletion or mutation of human Sar1b using the CRISPR-Cas9 system. We found that deletion or mutation of Sar1b in mice resulted in late-gestation lethality of homozygous embryos. Moreover, compared with WT mice, heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol, along with reduced CM secretion following gastric lipid gavage. Similarly, decreased expression of apolipoprotein B and microsomal triglyceride transfer protein was observed in correlation with the accumulation of mucosal lipids. Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion. Furthermore, genetically modified Sar1b affected intestinal lipid homeostasis as demonstrated by enhanced fatty acid β-oxidation and diminished lipogenesis through the modulation of transcription factors. This is the first reported mammalian animal model with human Sar1b genetic defects, which reproduces some of the characteristic CRD features and provides a direct cause-effect demonstration. |
| Databáze: | OpenAIRE |
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