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ATP-citrate lyase deficiency in the mouse
Anne P Beigneux1, Cynthia Kosinski, Bryant Gavino
1Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141, USA. abeigneux@gladstone.ucsf.edu
The Journal of Biological Chemistry
|December 10, 2003
Summary
ATP-citrate lyase (Acly) deficiency in mice impacts development, but heterozygous mice remain healthy. Acly knockout models reveal its crucial role in lipogenesis and neurotransmitter synthesis.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Diseases
Background:
- ATP-citrate lyase (Acly) synthesizes acetyl-CoA, a key molecule for cholesterol and triglyceride production.
- Acly is a potential therapeutic target for obesity and hyperlipidemias.
- Understanding Acly's in vivo function requires defining its expression patterns and the phenotype of Acly-deficient models.
Purpose of the Study:
- To create and characterize Acly knockout mice to define the enzyme's phenotype.
- To determine cell type-specific expression patterns of Acly.
- To elucidate the in vivo roles of Acly in lipid metabolism and other cellular processes.
Main Methods:
- Generation of Acly knockout mice with a beta-galactosidase reporter.
- Analysis of homozygous and heterozygous mouse phenotypes, including health, fertility, and lipid levels.
- Measurement of Acly mRNA and protein levels in various tissues and cell types (fibroblasts, hepatocytes).
- Assessment of cholesterol and triglyceride synthesis and gene expression.
- Beta-galactosidase staining to visualize Acly expression patterns.
Main Results:
- Homozygous Acly knockout mice exhibited early developmental lethality.
- Heterozygous mice were phenotypically normal, fertile, and normolipidemic on standard and high-fat diets.
- Reduced Acly levels in heterozygous mice did not significantly alter triglyceride or cholesterol synthesis.
- Acly expression was ubiquitous, with high levels in lipogenic tissues (liver on high-carb diet) and the developing brain.
- High Acly expression in adult brain cholinergic neurons suggests a role in acetylcholine synthesis.
Conclusions:
- Acly is essential for embryonic development.
- Reduced Acly levels in heterozygous mice do not impair systemic lipid homeostasis.
- Acly plays a significant role in de novo lipogenesis and is vital for acetylcholine synthesis in specific neuronal populations.
- The Acly knockout allele serves as a valuable tool for identifying tissues with high acetyl-CoA demand.