Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption
| العنوان: | Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption |
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| المؤلفون: | Ernest G. Seidman, Emile Levy, Schohraya Spahis, Marie Laure Kleme, Alain T. Sané, Edgard Delvin, Noël Peretti, Colette Deslandres, Carole Garofalo |
| المساهمون: | Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| المصدر: | Arteriosclerosis, Thrombosis, and Vascular Biology Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2017, 37 (12), pp.2243--2251. ⟨10.1161/ATVBAHA.117.310121⟩ |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Apolipoprotein E, [SDV]Life Sciences [q-bio], ACID-BINDING PROTEIN, GTPase, medicine.disease_cause, Hypobetalipoproteinemias, PRECHYLOMICRON, gene silencing, LIPID ABSORPTION, Chylomicrons, lipid metabolism, ABSORPTION, GTPase Gene, Intestinal Mucosa, Genetics, Mutation, intestines, biology, CHOLESTEROL, SAR1B, Gene Knockdown Techniques, SECRETION, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, ATP Binding Cassette Transporter 1, Chylomicron retention disease, EXPRESSION, chylomicron retention disease, ENDOPLASMIC-RETICULUM, Transfection, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Malabsorption Syndromes, medicine, Humans, Gene silencing, Triglycerides, Monomeric GTP-Binding Proteins, medicine.disease, MODEL, Enterocytes, 030104 developmental biology, Cell culture, biology.protein, CACO-2 CELLS, INTESTINAL EPITHELIAL-CELLS, mutation, Apolipoprotein B-48, apolipoproteins, TRANSPORT VESICLE |
| الوصف: | Background— Understanding the specific mechanisms of rare autosomal disorders has greatly expanded insights into the complex processes regulating intestinal fat transport. Sar1B GTPase is one of the critical proteins governing chylomicron secretion by the small intestine, and its mutations lead to chylomicron retention disease, despite the presence of Sar1A paralog. Objective— The central aim of this work is to examine the cause–effect relationship between Sar1B expression and chylomicron output and to determine whether Sar1B is obligatory for normal high-density lipoprotein biogenesis. Approach and Results— The SAR1B gene was totally silenced in Caco-2/15 cells using the zinc finger nuclease technique. SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%). The absence of expected chylomicron production collapse may be because of the compensatory SAR1A elevation observed in our experiments. Therefore, a double knockout of SAR1A and SAR1B was engineered in Caco-2/15 cells, which led to almost complete inhibition of triglycerides, apolipoprotein B-48, and chylomicron output. Further experiments with labeled cholesterol revealed the downregulation of high-density lipoprotein biogenesis in cells deficient in SAR1B or with the double knockout of the 2 SAR1 paralogs. Similarly, there was a fall in the movement of labeled cholesterol from cells to basolateral medium containing apolipoprotein A-I, thereby limiting newly synthesized high-density lipoprotein in genetically modified cells. The decreased cholesterol efflux was associated with impaired expression of ABCA1 (ATP-binding cassette subfamily A member 1). Conclusions— These findings demonstrate that the deletion of the 2 SAR1 isoforms is required to fully eliminate the secretion of chylomicron in vitro. They also underscore the limited high-density lipoprotein production by the intestinal cells in response to SAR1 knockout. |
| تدمد: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.117.310121 |
| DOI: | 10.1161/ATVBAHA.117.310121⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ac3048c104d7a8d2901846de86ae8835 https://doi.org/10.1161/atvbaha.117.310121 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ac3048c104d7a8d2901846de86ae8835 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244636 10795642 |
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| DOI: | 10.1161/atvbaha.117.310121 |