Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal

Area of Science:

• Biochemistry
• Metabolic Regulation
• Genetics

Background:

• Acetyl-CoA carboxylases (ACC1 and ACC2) are key enzymes in fatty acid metabolism, catalyzing acetyl-CoA to malonyl-CoA.
• Malonyl-CoA is a critical intermediate regulating fatty acid synthesis and oxidation.
• Previous studies showed ACC2 knockout mice are viable and impact fatty acid oxidation.

Purpose of the Study:

• To investigate the role of ACC1 in fatty acid metabolism using gene targeting.
• To determine the embryonic lethality and developmental impact of ACC1 deficiency.
• To further elucidate the distinct functions of ACC1 and ACC2 in malonyl-CoA metabolism.

Main Methods:

• Gene targeting to create ACC1 knockout mice.
• Analysis of heterozygous (Acc1(+/-)) mice for fertility, lifespan, body weight, mRNA, and protein levels.
• Assessment of fatty acid metabolism in Acc1(+/-) hepatocytes.
• Timed pregnancies to determine the embryonic lethality of ACC1 null embryos.

Main Results:

• Heterozygous Acc1(+/-) mice exhibited normal phenotypes but had half the ACC1 mRNA levels.
• No significant differences in fatty acid metabolism were observed in Acc1(+/-) hepatocytes.
• Homozygous Acc1(-/-) embryos were developmentally arrested by embryonic day 7.5 and died by E8.5, indicating embryonic lethality.
• Complete embryonic resorption occurred by E11.5 for Acc1(-/-) embryos.

Conclusions:

• ACC1 is essential for embryonic development, with complete loss leading to lethality.
• ACC1 and ACC2 play distinct and non-redundant roles in mammalian fatty acid metabolism.
• These findings support the hypothesis of independent malonyl-CoA pools regulated by ACC1 and ACC2.