Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease
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 ge...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227521000675 |
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| author | Nickolas Auclair Alain T. Sané Lena Ahmarani Nathalie Patey Jean-François Beaulieu Noel Peretti Schohraya Spahis Emile Levy |
| author_facet | Nickolas Auclair Alain T. Sané Lena Ahmarani Nathalie Patey Jean-François Beaulieu Noel Peretti Schohraya Spahis Emile Levy |
| author_sort | Nickolas Auclair |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T11:17:07Z |
| format | Article |
| id | doaj.art-ee8165d0dcfa4ef1b46a346787854c2c |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-24T11:17:07Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-ee8165d0dcfa4ef1b46a346787854c2c2022-12-21T16:58:21ZengElsevierJournal of Lipid Research0022-22752021-01-0162100085Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention diseaseNickolas Auclair0Alain T. Sané1Lena Ahmarani2Nathalie Patey3Jean-François Beaulieu4Noel Peretti5Schohraya Spahis6Emile Levy7Research Center, CHU Ste-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology & Physiology, Université de Montréal, Montreal, Quebec, CanadaResearch Center, CHU Ste-Justine, Université de Montréal, Montreal, Quebec, CanadaResearch Center, CHU Ste-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montreal, Quebec, CanadaResearch Center, CHU Ste-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Pathology, Université de Montréal, Montreal, Quebec, CanadaLaboratory of Intestinal Physiopathology, Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, CanadaDepartment of Pediatric Gastroenterology-Hepatology and Nutrition, Laboratory INSERM 1060 Cardiovascular Metabolism Endocrinology and Nutrition CarMEN, Lyon, FranceResearch Center, CHU Ste-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montreal, Quebec, CanadaResearch Center, CHU Ste-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology & Physiology, Université de Montréal, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada; For correspondence: Emile LevyChylomicron 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.http://www.sciencedirect.com/science/article/pii/S0022227521000675Sar1bgene defectsembryonic lethalitychylomicrondietary fatlipid metabolism |
| spellingShingle | Nickolas Auclair Alain T. Sané Lena Ahmarani Nathalie Patey Jean-François Beaulieu Noel Peretti Schohraya Spahis Emile Levy Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease Journal of Lipid Research Sar1b gene defects embryonic lethality chylomicron dietary fat lipid metabolism |
| title | Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease |
| title_full | Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease |
| title_fullStr | Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease |
| title_full_unstemmed | Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease |
| title_short | Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease |
| title_sort | sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease |
| topic | Sar1b gene defects embryonic lethality chylomicron dietary fat lipid metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S0022227521000675 |
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