title: Disruption of the acyl-CoA-binding protein gene delays hepatic adaptation to metabolic changes at weaning.
abstract: The acyl-CoA-binding protein (ACBP)/diazepam binding inhibitor is an intracellular protein that binds C(14)-C(22) acyl-CoA esters and is thought to act as an acyl-CoA transporter. In vitro analyses have indicated that ACBP can transport acyl-CoA esters between different enzymatic systems; however, little is known about the in vivo function in mammalian cells. We have generated mice with targeted disruption of ACBP (ACBP(-/-)). These mice are viable and fertile and develop normally. However, around weaning, the ACBP(-/-) mice go through a crisis with overall weakness and a slightly decreased growth rate. Using microarray analysis, we show that the liver of ACBP(-/-) mice displays a significantly delayed adaptation to weaning with late induction of target genes of the sterol regulatory element-binding protein (SREBP) family. As a result, hepatic de novo cholesterogenesis is decreased at weaning. The delayed induction of SREBP target genes around weaning is caused by a compromised processing and decreased expression of SREBP precursors, leading to reduced binding of SREBP to target sites in chromatin. In conclusion, lack of ACBP interferes with the normal metabolic adaptation to weaning and leads to delayed induction of the lipogenic gene program in the liver.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Neess
authors.forename: Maria
authors.initials: M
authors.lastname: Bloksgaard
authors.forename: Signe
authors.initials: S
authors.lastname: Bek
authors.forename: Ann-Britt
authors.initials: AB
authors.lastname: Marcher
authors.forename: Ida C
authors.initials: IC
authors.lastname: Elle
authors.forename: Torben
authors.initials: T
authors.lastname: Helledie
authors.forename: Marianne
authors.initials: M
authors.lastname: Due
authors.forename: Vasileios
authors.initials: V
authors.lastname: Pagmantidis
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
authors.forename: Johannes
authors.initials: J
authors.lastname: Wilbertz
authors.forename: Mogens
authors.initials: M
authors.lastname: Kruhøffer
authors.forename: Nils
authors.initials: N
authors.lastname: Færgeman
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn; D002784:Cholesterol / Q000096:biosynthesis; D002843:Chromatin / Q000378:metabolism; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D008660:Metabolism; D051379:Mice; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014886:Weaning
chemical_list: D002843:Chromatin; D026261:Diazepam Binding Inhibitor; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol