title: Induction of body weight loss through RNAi-knockdown of APOBEC1 gene expression in transgenic rabbits.
abstract: In the search of new strategies to fight against obesity, we targeted a gene pathway involved in energy uptake. We have thus investigated the APOB mRNA editing protein (APOBEC1) gene pathway that is involved in fat absorption in the intestine. The APOB gene encodes two proteins, APOB100 and APOB48, via the editing of a single nucleotide in the APOB mRNA by the APOBEC1 enzyme. The APOB48 protein is mandatory for the synthesis of chylomicrons by intestinal cells to transport dietary lipids and cholesterol. We produced transgenic rabbits expressing permanently and ubiquitously a small hairpin RNA targeting the rabbit APOBEC1 mRNA. These rabbits exhibited a moderately but significantly reduced level of APOBEC1 gene expression in the intestine, a reduced level of editing of the APOB mRNA, a reduced level of synthesis of chylomicrons after a food challenge, a reduced total mass of body lipids and finally presented a sustained lean phenotype without any obvious physiological disorder. Interestingly, no compensatory mechanism opposed to the phenotype. These lean transgenic rabbits were crossed with transgenic rabbits expressing in the intestine the human APOBEC1 gene. Double transgenic animals did not present any lean phenotype, thus proving that the intestinal expression of the human APOBEC1 transgene was able to counterbalance the reduction of the rabbit APOBEC1 gene expression. Thus, a moderate reduction of the APOBEC1 dependent editing induces a lean phenotype at least in the rabbit species. This suggests that the APOBEC1 gene might be a novel target for obesity treatment.
authors.affiliation: INRA UMR1198, Biologie du Développement et Reproduction, Jouy en Josas, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Jolivet
authors.affiliation: ObeTherapy Biotechnology, Evry, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Braud
authors.affiliation: INRA UMR1198, Biologie du Développement et Reproduction, Jouy en Josas, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: DaSilva
authors.affiliation: INRA UMR1313, Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Passet
authors.affiliation: INRA UMR1198, Biologie du Développement et Reproduction, Jouy en Josas, France.
authors.forename: Erwana
authors.initials: E
authors.lastname: Harscoët
authors.affiliation: INRA UMR1198, Biologie du Développement et Reproduction, Jouy en Josas, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Viglietta
authors.affiliation: INSERM UMR866, Université de Bourgogne, Dijon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.affiliation: INSERM UMR866, Université de Bourgogne, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.affiliation: INRA UMR1198, Biologie du Développement et Reproduction, Jouy en Josas, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Daniel-Carlier
authors.affiliation: INRA UMR1198, Biologie du Développement et Reproduction, Jouy en Josas, France.
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Houdebine
authors.affiliation: ObeTherapy Biotechnology, Evry, France.
authors.forename: Itzik
authors.initials: I
authors.lastname: Harosh
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D030801:Animals, Genetically Modified; D053283:Apolipoprotein B-48 / Q000097:blood; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D003564:Cytidine Deaminase / Q000235:genetics*; D059305:Diet, High-Fat; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D017393:RNA Editing / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011817:Rabbits; D019076:Transgenes; D014280:Triglycerides / Q000097:blood; D015431:Weight Loss
chemical_list: D053283:Apolipoprotein B-48; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014280:Triglycerides; D002784:Cholesterol; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; D003564:Cytidine Deaminase