title: Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis.
abstract: In animals, liver and white adipose are the main sites for the de novo fatty acid synthesis. Deletion of fatty acid synthase or acetyl-CoA carboxylase (ACC) 1 in mice resulted in embryonic lethality, indicating that the de novo fatty acid synthesis is essential for embryonic development. To understand the importance of de novo fatty acid synthesis and the role of ACC1-produced malonyl-CoA in adult mouse tissues, we generated liver-specific ACC1 knockout (LACC1KO) mice. LACC1KO mice have no obvious health problem under normal feeding conditions. Total ACC activity and malonyl-CoA levels were approximately 70-75% lower in liver of LACC1KO mice compared with that of the WT mice. In addition, the livers of LACC1KO mice accumulated 40-70% less triglycerides. Unexpectedly, when fed fat-free diet for 10 days, there was significant up-regulation of PPARgamma and several enzymes in the lipogenic pathway in the liver of LACC1KO mice compared with the WT mice. Despite the significant up-regulation of the lipogenic enzymes, including a >2-fold increase in fatty acid synthase mRNA, protein, and activity, there was significant decrease in the de novo fatty acid synthesis and triglyceride accumulation in the liver. However, there were no significant changes in blood glucose and fasting ketone body levels. Hence, reducing cytosolic malonyl-CoA and, therefore, the de novo fatty acid synthesis in the liver, does not affect fatty acid oxidation and glucose homeostasis under lipogenic conditions.
authors.affiliation: The Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Molecular and Cell Biology, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Mao
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: Huiguang
authors.initials: H
authors.lastname: Li
authors.forename: Lutfi
authors.initials: L
authors.lastname: Abu-Elheiga
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Gu
authors.forename: Tattym E
authors.initials: TE
authors.lastname: Shaikenov
authors.forename: Parichher
authors.initials: P
authors.lastname: Kordari
authors.forename: Subrahmanyam S
authors.initials: SS
authors.lastname: Chirala
authors.forename: William C
authors.initials: WC
authors.lastname: Heird
authors.forename: Salih J
authors.initials: SJ
authors.lastname: Wakil
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D004041:Dietary Fats / Q000627:therapeutic use; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000178:diet therapy; D051381:Rats; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004041:Dietary Fats; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D000103:Acetyl-CoA Carboxylase; D005947:Glucose