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 Ϸ70 -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 PPAR␥ 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.Cre-loxP ͉ fatty acid synthesis ͉ tissue-specific knockout I n eukaryotes, acetyl-CoA carboxylase (ACC) is a biotinylated enzyme that catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA. Fatty acid synthase (FAS), the multifunctional enzyme, catalyzes the synthesis of long-chain fatty acid, palmitate, by using acetyl-CoA as a primer, malonylCoA as a two-carbon donor for chain elongation, and NADPH for the reduction reactions. The synthesis of malonyl-CoA is the committed step toward the synthesis of fatty acids (1-5). In addition, malonyl-CoA also plays an important role in the regulation of fatty acid oxidation in the mitochondria as an inhibitor of the carnitine palmitoyl transferase 1, which performs the first step in the transfer of long-chain fatty acyl CoA into mitochondria for their oxidation (6, 7). Hence, malonyl-CoA participates in two opposing pathways, a substrate for fatty acid synthesis and a regulator of fatty acid oxidation. Lately, there are also reports that malonyl-CoA regulates orexigenic responses in hypothalamus (8) and insulin secretion by pancreatic ␤-islets (9, 10). Malonyl-CoA is generated by two isoforms of acetyl-CoA carboxylases, ACC1 and ACC2 of molecular mass 265 kDa and 280 kDa, respectively (11-16). ACC1 is a cytosolic enzyme, and ACC2 is associated with mitochondria (17). Although both isoforms are expressed in various tissues, ACC1 is predominantly expressed in lipogenic tissues such as liver, adipose, and lactating mammary gland, and ACC2 is predominantly expressed in muscle tissues and heart ...

aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues

“…The generation of the floxed ACC1 allele-containing mice has been described earlier (3). The mice (ACC1 lox/lox or lox ϩ/ϩ ) were bred with aP2-Cre mice (6) to disrupt ACC1 expression in adipose tissue.…”

“…To understand the importance of de novo fatty acid synthesis and the role of ACC1 in adult mouse tissues, we generated tissue-specific knockout mice using the Cre-loxP system (3). Mice with liverspecific knockout of ACC1 (LACC1KO) fed normal chow did not exhibit any significant physiological differences from wildtype (WT) mice (3). But when fed a fat-free diet, they accumulated significantly less triglyceride (TG) in the liver compared with their WT cohorts.…”

“…But when fed a fat-free diet, they accumulated significantly less triglyceride (TG) in the liver compared with their WT cohorts. Although inactivation of ACC1 resulted in 70-75% lower ACC activity in the liver, it did not affect either glucose homeostasis or hepatic fatty acid oxidation (3). When the LACC1KO mice were fed a fat-free diet for 10 days, there was an upregulation of PPAR␥ and several lipogenic enzymes in the liver, including a 2-fold increase in fatty acid synthase (FAS) mRNA, protein, and activity.…”

Quantitative proteomics study on the protective mechanism of phlorizin on hepatic damage in diabetic db/db mice

“…Acetyl-CoA carboxylase has two isoforms in rodents, ACACA and ACACB, which is a pivotal physiological regulator for both fatty acid synthesis and oxidation. Inhibition of ACACA decreases fatty acid synthesis and helps remedy systemic and tissue hyperlipidemia (20,21). ACAC2-null mice (ACAC2 -/-) not only have a higher fatty acid oxidation rate, but also lower hepatic steatosis (22).…”

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

“…ACC1, on the other hand, is an essential enzyme responsible for fatty acid synthesis in lipogenic tissues (liver and adipocytes). Deletion of the ACC1 gene in mice is embryo-lethal and has a pronounced effect on liver and adipose tissue lipid metabolism (16)(17)(18). Furthermore, lipogenesis is up-regulated in many tumors, increasing demand for ACC-made malonyl-CoA (19).…”