ATP-Citrate Lyase Deficiency in the Mouse

Anne P. Beigneux, Cynthia Kosinski, Bryant Gavino, Jay D. Horton, William C. Skarnes, Stephen G. Young

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

ATP-citrate lyase (Acly) is one of two cytosolic enzymes that synthesize acetyl-coenzyme A (CoA). Because acetyl-CoA is an essential building block for cholesterol and triglycerides, Acly has been considered a therapeutic target for hyperlipidemias and obesity. To define the phenotype of Acly-deficient mice, we created Acly knockout mice in which a β-galactosidase marker is expressed from Acly regulatory sequences. We also sought to define the cell type-specific expression patterns o£ of Acly to further elucidate the in vivo roles of the enzyme. Homozygous Acly knockout mice died early in development. Heterozygous mice were healthy, fertile, and normolipidemic on both chow and high fat diets, despite expressing half-normal amounts of Acly mRNA and protein. Fibroblasts and hepatocytes from heterozygous Acly mice contained half-normal amounts of Acly mRNA and protein, but this did not perturb triglyceride and cholesterol synthesis or the expression of lipid biosynthetic genes regulated by sterol regulatory element-binding proteins. The expression of acetyl-CoA synthetase 1, another cytosolic enzyme for producing acetyl-CoA, was not up-regulated. As judged by β-galactosidase staining, Acly was expressed ubiquitously but was expressed particularly highly in tissues with high levels of lipogenesis, such as in the livers of mice fed a high-carbohydrate diet. β-Galactosidase staining was intense in the developing brain, in keeping with the high levels of de novo lipogenesis of the tissue. In the adult brain, β-galactosidase staining was in general much lower, consistent with reduced levels of lipogenesis; however, β-galactosidase expression remained very high in cholinergic neurons, likely reflecting the importance of Acly in generating acetyl-CoA for acetylcholine synthesis. The Acly knockout allele is useful for identifying cell types with a high demand for acetyl-CoA synthesis.

Original languageEnglish (US)
Pages (from-to)9557-9564
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number10
DOIs
StatePublished - Mar 5 2004

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ATP Citrate (pro-S)-Lyase
Galactosidases
Acetyl Coenzyme A
Lipogenesis
Nutrition
Staining and Labeling
Knockout Mice
Brain
Triglycerides
Enzymes
Acetate-CoA Ligase
Sterol Regulatory Element Binding Proteins
Cholesterol
Tissue
Messenger RNA
Cholinergic Neurons
High Fat Diet
Fibroblasts
Hyperlipidemias

ASJC Scopus subject areas

  • Biochemistry

Cite this

Beigneux, A. P., Kosinski, C., Gavino, B., Horton, J. D., Skarnes, W. C., & Young, S. G. (2004). ATP-Citrate Lyase Deficiency in the Mouse. Journal of Biological Chemistry, 279(10), 9557-9564. https://doi.org/10.1074/jbc.M310512200

ATP-Citrate Lyase Deficiency in the Mouse. / Beigneux, Anne P.; Kosinski, Cynthia; Gavino, Bryant; Horton, Jay D.; Skarnes, William C.; Young, Stephen G.

In: Journal of Biological Chemistry, Vol. 279, No. 10, 05.03.2004, p. 9557-9564.

Research output: Contribution to journalArticle

Beigneux, AP, Kosinski, C, Gavino, B, Horton, JD, Skarnes, WC & Young, SG 2004, 'ATP-Citrate Lyase Deficiency in the Mouse', Journal of Biological Chemistry, vol. 279, no. 10, pp. 9557-9564. https://doi.org/10.1074/jbc.M310512200
Beigneux AP, Kosinski C, Gavino B, Horton JD, Skarnes WC, Young SG. ATP-Citrate Lyase Deficiency in the Mouse. Journal of Biological Chemistry. 2004 Mar 5;279(10):9557-9564. https://doi.org/10.1074/jbc.M310512200
Beigneux, Anne P. ; Kosinski, Cynthia ; Gavino, Bryant ; Horton, Jay D. ; Skarnes, William C. ; Young, Stephen G. / ATP-Citrate Lyase Deficiency in the Mouse. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 10. pp. 9557-9564.
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