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Acyl-CoA binding protein gene ablation induces pre-implantation embryonic lethality in mice.

ABSTRACT: Unique among the intracellular lipid binding proteins, acyl-CoA binding protein (ACBP) exclusively binds long-chain fatty acyl-CoAs (LCFA-CoAs). To test if ACBP is an essential protein in mammals, the ACBP gene was ablated by homologous recombination in mice. While ACBP heterozygotes appeared phenotypically normal, intercrossing of the heterozygotes did not produce any live homozygous deficient (null) ACBP((-/-)) pups. Heterozygous and wild type embryos were detected at all post-implantation stages, but no homozygous ACBP-null embryos were obtained-suggesting that an embryonic lethality occurred at a pre-implantation stage of development, or that embryos never formed. While ACBP-null embryos were not detected at any blastocyst stage, ACBP-null embryos were detected at the morula (8-cell), cleavage (2-cell), and zygote (1-cell) pre-implantation stages. Two other LCFA-CoA binding proteins, sterol carrier protein-2 (SCP-2) and sterol carrier protein-x (SCP-x) were significantly upregulated at these stages. These findings demonstrate for the first time that ACBP is an essential protein required for embryonic development and its loss of function may be initially compensated by concomitant upregulation of two other LCFA-CoA binding proteins, but only at the earliest pre-implantation stages. The fact that ACBP is the first known intracellular lipid binding protein whose deletion results in embryonic lethality suggests its vital importance in mammals.

SUBMITTER: Landrock D

PROVIDER: S-EPMC2997683 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Acyl-CoA binding protein gene ablation induces pre-implantation embryonic lethality in mice.

Landrock Danilo D Atshaves Barbara P BP McIntosh Avery L AL Landrock Kerstin K KK Schroeder Friedhelm F Kier Ann B AB

Lipids 20100618 7

Unique among the intracellular lipid binding proteins, acyl-CoA binding protein (ACBP) exclusively binds long-chain fatty acyl-CoAs (LCFA-CoAs). To test if ACBP is an essential protein in mammals, the ACBP gene was ablated by homologous recombination in mice. While ACBP heterozygotes appeared phenotypically normal, intercrossing of the heterozygotes did not produce any live homozygous deficient (null) ACBP((-/-)) pups. Heterozygous and wild type embryos were detected at all post-implantation sta ...[more]

PMID: 20559753

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Project description:ObjectiveThe family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform.MethodsTo elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5 (-/-) ).ResultsAblation of ACSL5 reduced ACSL activity by ∼80% in jejunal mucosa, ∼50% in liver, and ∼37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5 (-/-) , as compared to control ACSL5 (loxP/loxP) , mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5 (-/-) had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5 (-/-) mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (∼16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (∼13-fold) were increased in ACSL5 (-/-) as compared to ACSL5 (loxP/loxP) . Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5 (-/-) mice as compared to control mice.ConclusionsIn summary, ACSL5 (-/-) mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.

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Acyl-CoA binding protein gene ablation induces pre-implantation embryonic lethality in mice.

Publications

Acyl-CoA binding protein gene ablation induces pre-implantation embryonic lethality in mice.

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