SAR1B GTPase is necessary to protect intestinal cells from disorders of lipid homeostasis, oxidative stress, and inflammation

Genetic defects in SAR1B GTPase inhibit chylomicron (CM) trafficking to the Golgi and result in a huge intraenterocyte lipid accumulation with a failure to release CMs and liposoluble vitamins into the blood circulation. The central aim of this study is to test the hypothesis that SAR1B deletion (SAR1B−/−) disturbs enterocyte lipid homeostasis (e.g., FA β-oxidation and lipogenesis) while promoting oxidative stress and inflammation. Another issue is to compare the impact of SAR1B−/− to that of its paralogue SAR1A−/− and combined SAR1A−/−/B−/−. To address these critical issues, we have generated Caco-2/15 cells with a knockout of SAR1A, SAR1B, or SAR1A/B genes. SAR1B−/− results in lipid homeostasis disruption, reflected by enhanced mitochondrial FA β-oxidation and diminished lipogenesis in intestinal absorptive cells via the implication of PPARα and PGC1α transcription factors. Additionally, SAR1B−/−cells, which mimicked enterocytes of CM retention disease, spontaneously disclosed inflammatory and oxidative characteristics via the implication of NF-κB and NRF2. In most conditions, SAR1A−/− cells showed a similar trend, albeit less dramatic, but synergetic effects were observed with the combined defects of the two SAR1 paralogues. In conclusion, SAR1B and its paralogue are needed not only for CM trafficking but also for lipid homeostasis, prooxidant/antioxidant balance, and protection against inflammatory processes. Genetic defects in SAR1B GTPase inhibit chylomicron (CM) trafficking to the Golgi and result in a huge intraenterocyte lipid accumulation with a failure to release CMs and liposoluble vitamins into the blood circulation. The central aim of this study is to test the hypothesis that SAR1B deletion (SAR1B−/−) disturbs enterocyte lipid homeostasis (e.g., FA β-oxidation and lipogenesis) while promoting oxidative stress and inflammation. Another issue is to compare the impact of SAR1B−/− to that of its paralogue SAR1A−/− and combined SAR1A−/−/B−/−. To address these critical issues, we have generated Caco-2/15 cells with a knockout of SAR1A, SAR1B, or SAR1A/B genes. SAR1B−/− results in lipid homeostasis disruption, reflected by enhanced mitochondrial FA β-oxidation and diminished lipogenesis in intestinal absorptive cells via the implication of PPARα and PGC1α transcription factors. Additionally, SAR1B−/−cells, which mimicked enterocytes of CM retention disease, spontaneously disclosed inflammatory and oxidative characteristics via the implication of NF-κB and NRF2. In most conditions, SAR1A−/− cells showed a similar trend, albeit less dramatic, but synergetic effects were observed with the combined defects of the two SAR1 paralogues. In conclusion, SAR1B and its paralogue are needed not only for CM trafficking but also for lipid homeostasis, prooxidant/antioxidant balance, and protection against inflammatory processes. The small intestine is the essential site for the transport of alimentary fat in the form of lipoproteins. After the digestive phase, the lipolytic products in the lumen are absorbed by enterocytes that possess the unique ability to elaborate chylomicrons (CMs), the largest triglyceride (TG)-rich lipoprotein and dietary lipid vehicle (1Levy E. Insights from human congenital disorders of intestinal lipid metabolism.J. Lipid Res. 2015; 56: 945-962Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 2Mansbach II, C.M. Siddiqi S. Control of chylomicron export from the intestine.Am. J. Physiol. Gastrointest. Liver Physiol. 2016; 310: G659-G668Crossref PubMed Scopus (38) Google Scholar). CM assembly within epithelial absorptive cells is a multistep pathway that includes the translocation of lipolytic products from the apical membrane to the ER by cytosolic fatty acid-binding proteins (FABPs), lipid esterification, synthesis, and the posttranslational modification of different apos, especially apoB-48, as well as the packaging of lipid and apo components into pre-CM particles (3Kumar N.S. Mansbach II, C.M. Prechylomicron transport vesicle: isolation and partial characterization.Am. J. Physiol. 1999; 276: G378-G386Crossref PubMed Google Scholar, 4Mansbach C.M. Siddiqi S.A. The biogenesis of chylomicrons.Annu. Rev. Physiol. 2010; 72: 315-333Crossref PubMed Scopus (142) Google Scholar, 5Siddiqi S. Saleem U. Abumrad N.A. Davidson N.O. Storch J. Siddiqi S.A. Mansbach II, C.M. A novel multiprotein complex is required to generate the prechylomicron transport vesicle from intestinal ER.J. Lipid Res. 2010; 51: 1918-1928Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). It is only under these specific conditions that CM particles move huge amounts of dietary fat into the blood circulation via the lymphatic system. Accidents of nature reveal the intracellular roles of key proteins in CM assembly and secretion (6Jones B. Jones E.L. Bonney S.A. Patel H.N. Mensenkamp A.R. Eichenbaum-Voline S. Rudling M. Myrdal U. Annesi G. Naik S. et al.Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.Nat. Genet. 2003; 34: 29-31Crossref PubMed Scopus (291) Google Scholar). For example, deciphering chylomicron retention disease (CRD) afforded new insight into the crucial functions of SAR1B GTPase, the defects of which lead to severe fat malabsorption, hypocholesterolemia, extensive steatorrhea, and significant failure to thrive in children (7Peretti N. Sassolas A. Roy C.C. Deslandres C. Charcosset M. Castagnetti J. Pugnet-Chardon L. Moulin P. Labarge S. Bouthillier L. et al.Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.Orphanet J. Rare Dis. 2010; 5: 24Crossref PubMed Scopus (89) Google Scholar, 8Bouma M.E. Infante R. Jos J. Schmitz J. Chylomicron retention disease.Gastroenterology. 1988; 94: 554-556Abstract Full Text PDF PubMed Scopus (10) Google Scholar) with developmental abnormalities in various organs (9Levic D.S. Minkel J.R. Wang W.D. Rybski W.M. Melville D.B. Knapik E.W. Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.J. Mol. Med. (Berl.). 2015; 93: 165-176Crossref PubMed Scopus (37) Google Scholar). It is now well established that mutations in SAR1B (SARA2) gene encoding the SAR1B GTPase protein prevent the coat protein complex II (COPII) from producing mature CM-contained vesicles endowed with the ability to bud from the ER and reach the Golgi apparatus (6Jones B. Jones E.L. Bonney S.A. Patel H.N. Mensenkamp A.R. Eichenbaum-Voline S. Rudling M. Myrdal U. Annesi G. Naik S. et al.Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.Nat. Genet. 2003; 34: 29-31Crossref PubMed Scopus (291) Google Scholar, 10Magnolo L. Najah M. Fancello T. Di Leo E. Pinotti E. Brini I. Gueddiche N.M. Calandra S. Slimene N.M. Tarugi P. Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia.Gene. 2013; 512: 28-34Crossref PubMed Scopus (24) Google Scholar, 11Treepongkaruna S. Chongviriyaphan N. Suthutvoravut U. Charoenpipop D. Choubtum L. Wattanasirichaigoon D. Novel missense mutations of SAR1B gene in an infant with chylomicron retention disease.J. Pediatr. Gastroenterol. Nutr. 2009; 48: 370-373Crossref PubMed Scopus (15) Google Scholar). Therefore, the genetic defects in SAR1B inhibit the step of CM trafficking to the Golgi and result in a huge accumulation of intraenterocyte TG with a failure to release CM and liposoluble vitamins into the blood circulation (2Mansbach II, C.M. Siddiqi S. Control of chylomicron export from the intestine.Am. J. Physiol. Gastrointest. Liver Physiol. 2016; 310: G659-G668Crossref PubMed Scopus (38) Google Scholar, 12Hussain M.M. Intestinal lipid absorption and lipoprotein formation.Curr. Opin. Lipidol. 2014; 25: 200-206Crossref PubMed Scopus (196) Google Scholar). Recently, we have shown that the total silencing of SAR1B(SAR1B−/−) lessens but does not extinguish the output of TG-rich lipoproteins (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar) in intestinal cells, as is the case for patients with CRD (6Jones B. Jones E.L. Bonney S.A. Patel H.N. Mensenkamp A.R. Eichenbaum-Voline S. Rudling M. Myrdal U. Annesi G. Naik S. et al.Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.Nat. Genet. 2003; 34: 29-31Crossref PubMed Scopus (291) Google Scholar, 10Magnolo L. Najah M. Fancello T. Di Leo E. Pinotti E. Brini I. Gueddiche N.M. Calandra S. Slimene N.M. Tarugi P. Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia.Gene. 2013; 512: 28-34Crossref PubMed Scopus (24) Google Scholar, 14Charcosset M. Sassolas A. Peretti N. Roy C.C. Deslandres C. Sinnett D. Levy E. Lachaux A. Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein.Mol. Genet. Metab. 2008; 93: 74-84Crossref PubMed Scopus (71) Google Scholar). It is only through the combined depletion of SAR1B and SAR1A that CM delivery is fully eliminated. Additionally, SAR1B−/− modulates the protein expression of intestinal FABP, hepatic FABP, and the microsomal TG transfer protein while decreasing ATP-binding cassette transporter A1, thereby affecting enterocyte and lipoprotein (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar). the of CM and to SAR1B lipid homeostasis in enterocytes an we have as to the impact of lipid accumulation on intracellular FA β-oxidation on the and on lipogenesis on the in the study is the of intracellular oxidative stress and by SAR1B the of or the the SAR1 SAR1A and SAR1B, in the enterocyte lipid homeostasis an Therefore, the aim of this study is to test the hypothesis that lipid accumulation intracellular lipid and lipogenesis) and and via the of transcription factors. To address these critical issues, we have generated Caco-2/15 cells with a of or combined genes. In these cells, we mitochondrial oxidative with a on critical and lipogenesis with a on and fatty by protein and by the of transcription factors. as (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar). In against human SAR1B were in Caco-2/15 cells to the to generate an SAR1B−/− SAR1A and protein were also in to SAR1A−/− SAR1 established by SAR1B−/− cells with the SAR1A and via The for and were for through and cells were as Caco-2/15 cells were as A. Seidman E. Spahis S. Garofalo C. A. Levy E. in intestinal GTPase and in 2015; PubMed Scopus Google Scholar). were with in and For cells were a of on to cells were for to fully into a with by protein expression as a of cell M.L. A.T. Garofalo C. Levy E. gene with in human intestinal epithelial cells oxidative stress and J. Biol. 2016; PubMed Scopus (15) Google Scholar). also to the and the S. cell and 2013; PubMed Scopus Google Scholar). Caco-2/15 cells were in with The cells were with and for in the of After the the cells were and with a in a and were by the of and The to the and the in a with by with a protein the and results were as of cell Caco-2/15 cells were in The cells were and in to in with were into a in which a of to the under After the to the cells, which were for an with to the the the of were to for were and in the for the of to the an of Caco-2/15 cells were with and the with Caco-2/15 cells were and for with an with a and a of and were The cell were from with and of the The of a lipid in Caco-2/15 cells with in cell by with The were protein with a were with an of for After to the gene with and under a The in with a with a In the in the cell by the expression of Caco-2/15 cells were with for were in and of total proteins were to or and were with the specific of SAR1A/B by of protein protein NF-κB and as an After with the were were a are as the of protein to in the from the the and were a an of After generated from of total the The an for by of for and and for genes were by the of expression of were by the (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar). are as the of two in were by To the impact of SAR1 on FA we generated Caco-2/15 cells with the of SAR1A, SAR1B, or the combined two as (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar). and protein expression the total of genes of in Caco-2/15 we that these genetic not cell and or the as by and (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar). that genetic does not protein a of cell in cells with also showed and Caco-2/15 cells Therefore, the different are well to the of SAR1 genes in intestinal lipid A significant of in SAR1B−/− cells and a in in cells with were lipid In of these we the of expression of a protein is to the from oxidative protein in cells, to in cells with to a transcription that functions as the key of the gene cells showed a in protein which to in SAR1B−/− and with the of the a of in intestinal In of lipid to inflammation. The in cells the gene and protein with in NF-κB is a key of we its in Caco-2/15 cells showed a in NF-κB protein expression in SAR1A−/− and SAR1B−/− that with an in cells significant in protein expression The of the the of NF-κB in To test the impact of on mitochondrial oxidative we intestinal cells with the of the shown in the of the in to a similar of in Caco-2/15 cells with the results not reach the the of SAR1 to a in with which are the of FA were also in cells with results to the mitochondrial expression of and these proteins are of the FA β-oxidation A of gene and protein expression in to and we not in gene expression in Caco-2/15 cells, the of protein expression disclosed in Caco-2/15 cells to cells with SAR1B−/− and and the these a of FA through promoting the of while the protein of and two transcription for the expression of mitochondrial FA genes in conditions of SAR1 showed a of and protein with an of to and to in also the protein expression of and the protein in cells as a of mitochondrial and to mitochondrial by by and by of Caco-2/15 to only an in in were with to in shown in to in SAR1B−/− and cells in SAR1A−/− an in and protein a central of we its gene which in cells to an of in cells also the protein expression of in Caco-2/15 shown in the deletion of SAR1 protein expression to a significant in the of intracellular lipid and we the of cells and a protein expression in SAR1A−/− cells and an expression in SAR1B−/− and cells CRD is by intestinal fat transport to the to and we have that the deficiency of SAR1B to lipid homeostasis in a significant of FA β-oxidation in with the of key mitochondrial as and by the expression of the transcription and the SAR1 deletion a central of homeostasis, as well as protein which as a of the against a in protein an of lipid SAR1 NF-κB and lipogenesis diminished in to SAR1 as reflected by the of and The critical issue the study to the deletion of SAR1B, the gene for CRD or disease E. R. G. Seidman E. M. Roy C.C. Intestinal synthesis, and lipoproteins in chylomicron retention disease.J. Lipid Res. Full Text PDF PubMed Google Scholar, C.C. Levy E. A. J. J. P. et hypocholesterolemia, and enterocytes with intestinal B. Chylomicron retention disease.Gastroenterology. Full Text PDF PubMed Scopus Google intracellular lipid and intestinal cells, showed intracellular lipid retention and to CMs (13Sané A.T. Seidman E. Peretti N. Kleme M.L. Delvin E. Deslandres C. Garofalo C. Spahis S. Levy E. Understanding chylomicron retention disease through Sar1b Gtpase gene disruption: insight from cell culture.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 2243-2251Crossref PubMed Scopus (23) Google Scholar, E. R. G. Seidman E. M. Roy C.C. Intestinal synthesis, and lipoproteins in chylomicron retention disease.J. Lipid Res. Full Text PDF PubMed Google Scholar, C.C. Levy E. A. J. J. P. et hypocholesterolemia, and enterocytes with intestinal B. Chylomicron retention disease.Gastroenterology. Full Text PDF PubMed Scopus Google Scholar). In the molecular of this the COPII to form a the vesicles CM in the pathway for and with thereby intestinal CM (6Jones B. Jones E.L. Bonney S.A. Patel H.N. Mensenkamp A.R. Eichenbaum-Voline S. Rudling M. Myrdal U. Annesi G. Naik S. et al.Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.Nat. Genet. 2003; 34: 29-31Crossref PubMed Scopus (291) Google Scholar). is with the severe deficiency of and vitamins a fat E. R. G. Seidman E. M. Roy C.C. Intestinal synthesis, and lipoproteins in chylomicron retention disease.J. Lipid Res. Full Text PDF PubMed Google Scholar, C.C. Levy E. A. J. J. P. et hypocholesterolemia, and enterocytes with intestinal B. Chylomicron retention disease.Gastroenterology. Full Text PDF PubMed Scopus Google Scholar). 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PubMed Scopus Google we its protein expression in Caco-2/15 showed a significant in SAR1B−/− and but with a in different for the two paralogues. that the of intracellular have for the intestinal of CRD patients in of and the of cell and not defects in Caco-2/15 this in of CRD patients or in the small intestine of in the In conclusion, SAR1B silencing results not only in a failure to and vitamins in the form of CMs but also in lipid homeostasis disruption, reflected by enhanced mitochondrial FA β-oxidation and diminished lipogenesis in intestinal absorptive Additionally, SAR1B−/− cells, which mimicked enterocytes of spontaneously disclosed inflammatory and oxidative In most conditions, the combined in the of the The of the of for the SAR1A/B with protein protein chylomicron coat protein complex II chylomicron retention disease fatty acid-binding protein oxidative stress protein triglyceride protein

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