Hepatic De Novo Lipogenesis Is Present in Liver-Specific ACC1-Deficient Mice

Abstract

Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes carboxylation of acetyl-CoA to form malonylCoA. In mammals, two isozymes exist with distinct physiological roles: cytosolic ACC1 participates in de novo lipogenesis (DNL), and mitochondrial ACC2 is involved in negative regulation of mitochondrial ␤-oxidation. Since systemic ACC1 null mice were embryonic lethal, to clarify the physiological role of ACC1 in hepatic DNL, we generated the liver-specific ACC1 null mouse by crossbreeding of an Acc1 lox(ex46) mouse, in which exon 46 of Acc1 was flanked by two loxP sequences and the liver-specific Cre transgenic mouse. In liver-specific ACC1 null mice, neither hepatic Acc1 mRNA nor protein was detected. However, to compensate for ACC1 function, hepatic ACC2 protein and activity were induced 1.4 and 2.2 times, respectively. Surprisingly, hepatic DNL and malonyl-CoA were maintained at the same physiological levels as in wild-type mice. Furthermore, hepatic DNL was completely inhibited by an ACC1/2 dual inhibitor, 5-tetradecyloxyl-2-furancarboxylic acid. These results strongly demonstrate that malonyl-CoA from ACC2 can access fatty acid synthase and become the substrate for the DNL pathway under the unphysiological circumstances that result with ACC1 disruption. Therefore, there does not appear to be strict compartmentalization of malonyl-CoA from either of the ACC isozymes in the liver.Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, which is a key molecule in the control of intracellular fatty acid metabolism (13,16,27). ACC has two major isozymes that have different physiological roles based on their distinct subcellular distributions (2). A cytosolic enzyme, ACC1 (ACC␣; molecular mass, 265 kDa), supplies malonyl-CoA to fatty acid synthase (FAS) and is committed to de novo lipogenesis (DNL) in many tissues via subsequent nutritional and hormonal regulation (3,16,27). In contrast, ACC2 (ACC␤; molecular mass, 280 kDa) is anchored to the mitochondrial surface via a unique N-terminal domain that includes 20 hydrophobic amino acids (1, 2). ACC2 produces malonyl-CoA on the mitochondrial surface. It is well known that malonylCoA is a potent endogenous inhibitor of carnitine palmitoyl transferase 1 (CPT-1), which is also located on the mitochondrial surface (21, 26). Thus, ACC2 indirectly prevents the influx of fatty acids into the mitochondria and their subsequent ␤-oxidation (4).ACC1 is ubiquitously expressed in many tissues, but higher levels occur in lipogenic tissues, including the liver and adipose tissue (8). In fact, in animals, Acc1 gene expression and ACC activity are markedly induced either by high carbohydrate feeding or hyperinsulinemia in animals and result in increases in adiposity, lipoprotein secretion, and hepatic fat content (16). It is expected that ACC1 blockade should reduce flux through the DNL pathway in lipogenic tissues and thus reduce adiposity, lipoprotein secretion, and fatty liver (11,23). It is therefore plausible that ACC1 inh...

Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease

“…To further elucidate the role of ACC1 in liver de novo lipogenesis, two liver-specific ACC1-knockout mouse models have been generated using Cre- lox/P system (63; 64). Mao et al reported that on standard chow diet ACC1 knockout mice accumulate less triglycerides in their livers and have decreased malonyl-CoA levels.…”

“…When fed a fat-free diet for 10 days, mice with liver specific ACC1 knockout had significant up-regulation of several enzymes in the fatty acid synthesis pathway, again indicating that dietary carbohydrates may compensate for a loss of single DNL enzyme (63). Surprisingly, in a study by Harada at al., liver specific ACC1 knockout did not alter hepatic DNL or malonyl-CoA levels, however, hepatic DNL was completely inhibited by the dual ACC1 and ACC2 inhibitor, 5-tetradecyloxyl-2-furancarboxylic acid (64). In both of these models compensatory upregulation in ACC2 expression was observed, making the interpretation of ACC1 knockout in these studies challenging.…”

Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group

“…2 Recent studies reported by Harada et al indicate that hepatic ACC2 could partially cover ACC1 function as a backup system. 3 Consequently, reduction of malonyl-CoA levels in these tissues by ACC1/2 non-selective inhibitors is expected to reduce de novo fatty acid synthesis and triglyceride (TG)-rich lipoprotein secretions in liver while increasing fatty acid b-oxidation in liver and skeletal muscle. Therefore, an ACC1/2 non-selective inhibitor might provide a novel therapeutic approach for treating various metabolic disorders.…”

Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene

“…Liver lipids were extracted and analyzed as described previously (6). De novo lipogenesis in mouse primary hepatocytes was analyzed using sodium [2-14 C]acetate (PerkinElmer Life Sciences) as described previously (65). Lipogenic activity was presented as normalized radioactivity (counts per min (cpm)) to protein amount.…”