Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal

Abstract

Acetyl-CoA carboxylases (ACC1 and ACC2) catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a pivotal role in the regulation of fatty acid metabolism. We previously reported that ACC2 null mice are viable, and that ACC2 plays an important role in the regulation of fatty acid oxidation through the inhibition of carnitine palmitoyltransferase I, a mitochondrial component of the fatty-acyl shuttle system. Herein, we used gene targeting to knock out the ACC1 gene. The heterozygous mutant mice (Acc1 ؉/؊ ) had normal fertility and lifespans and maintained a similar body weight to that of their wild-type cohorts. The mRNA level of ACC1 in the tissues of Acc1 ؉/؊ mice was half that of the wild type; however, the protein level of ACC1 and the total malonyl-CoA level were similar. In addition, there was no difference in the acetate incorporation into fatty acids nor in the fatty acid oxidation between the hepatocytes of Acc1 ؉/؊ mice and those of the wild type. In contrast to Acc2 ؊/؊ mice, Acc1 ؊/؊ mice were not detected after mating. Timed pregnancies of heterozygotes revealed that Acc ؊/؊ embryos are already undeveloped at embryonic day (E)7.5, they die by E8.5, and are completely resorbed at E11.5. Our previous results of the ACC2 knockout mice and current studies of ACC1 knockout mice further confirm our hypotheses that malonyl-CoA exists in two independent pools, and that ACC1 and ACC2 have distinct roles in fatty acid metabolism. malonyl-CoAA cetyl-CoA carboxylases (ACCs) are biotin-containing enzymes that catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a key role in the regulation of fatty acid metabolism. In addition, malonylCoA, as a precursor of the synthesis of long-chain fatty acids, has been implicated as a signal molecule for insulin secretion from the pancreatic ␤-islets (1, 2). The role that ACC plays in energy metabolism in lipogenic tissues (liver and adipose) and in oxidative tissues (liver, heart, and skeletal muscle) have become the focus of many studies (3-8). In lipogenic tissues, malonylCoA is the C 2 -unit donor for de novo synthesis of long-chain fatty acids catalyzed by fatty acid synthase (FAS) and for the chain elongation of fatty acid to very long-chain fatty acids. Moreover, increasing evidence suggests that malonyl-CoA is a regulator of fatty acid oxidation through the inhibition of carnitine palmitoyltransferase I, an enzyme that controls the entry of long-chain fatty acids into the mitochondria for ␤-oxidation (3). In animals, including humans, ACC1 (M r ϭ 265,000) and ACC2 (M r ϭ 280,000) are the two isoforms of acetyl-CoA carboxylase that are encoded by two separate genes, ACC1 and ACC2, respectively, and they display distinct tissue distribution (9-12). ACC1 is abundant in lipogenic tissues, such as liver and adipose tissue, whereas ACC2 is highly expressed in heart, skeletal muscle, and liver (9, 10). Recently, Loftus et al. (13) proposed that malonylCoA plays a role in the central ne...

The role of rapid lipogenesis in insulin secretion: Insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells

“…This showed that of the two isoforms of acetyl-CoA carboxylase, the enzyme that converts acetyl-CoA into malonyl-CoA, ACC1 is the major, or only, isoform present in the beta cell. ACC1 is the predominant isoform of the enzyme in lipogenic tissues, such as liver and adipose tissue, whereas the other isoform, ACC2, is found in oxidative tissues, such as cardiac muscle and skeletal muscle [18][19][20]. We also observed that rat pancreatic islets and INS-1 832/13 cells possess a fairly high level of fatty acid synthase.…”

“…Malonyl-CoA is also a key regulator of fatty acid oxidation because it is an allosteric inhibitor of carnitine palmitoyltransferase-1 (CPT-1), localized in the outer surface of the inner mitochondrial membrane, where CPT-1 is involved in the transport of long chain acyl-CoAs acids into mitochondria for oxidation. Work from the Wakil group has shown that ACC2 is localized at the mitochondrial membrane, situated so that the malonyl-CoA it synthesizes controls the transport of long chain fatty acyl-CoA by the membrane bound CPT-1 [18,19]. Wakil's data are consistent with ACC1 producing malonyl-CoA for lipogenesis and ACC2 producing malonyl-CoA for inhibition of long chain acyl-CoA uptake and their oxidation into mitochondria [18,20].…”

“…MalonylCoA is formed by the carboxylation of acetyl-CoA catalyzed by acetyl-CoA carboxylase (ACC). There are two isoforms of ACC encoded by two separate genes in animals including humans; ACC1 (M r = 265,000) which is abundant in the cytosol of lipogenic tissues, such as liver and adipose tissue, and ACC2 (M r = 280,000) which is abundant in oxidative tissues, such as heart and skeletal muscle, and is present to a small degree in the liver [18][19][20]. (In line with this correlation is the fact that cardiac muscle possesses little or no pyruvate carboxylase activity, unlike islets and liver, and is capable of little or no anaplerosis [2,39].)…”

“…Work from the Wakil group has shown that ACC2 is localized at the mitochondrial membrane, situated so that the malonyl-CoA it synthesizes controls the transport of long chain fatty acyl-CoA by the membrane bound CPT-1 [18,19]. Wakil's data are consistent with ACC1 producing malonyl-CoA for lipogenesis and ACC2 producing malonyl-CoA for inhibition of long chain acyl-CoA uptake and their oxidation into mitochondria [18,20]. The finding of the current study ( Figure 2) that ACC1 is the predominant, or only, ACC isoform in pancreatic islets and INS-1 832/13 cells, and a previous observation that the 265 kDa isoform of ACC is the major isoform present in rat islets and INS-1 cells [40], are consistent with the idea that the beta cell is a lipogenic tissue.…”

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).…”