Acetyl-CoA Carboxylase β Gene Is Regulated by Sterol Regulatory Element-binding Protein-1 in Liver

Abstract

Acetyl-CoA carboxylase (ACC) exists as two major isoforms originated from separate genes: ACC␣ (or ACC1) and ACC␤ (or ACC2). Previous data revealed that ACC␤ has two forms of mRNA with different 5-untranslated regions derived by different usage of promoters, I and II, in human. In this study, we revealed that ACC␤ expression in liver is markedly stimulated by food intake at the transcriptional level. In the process of this induction in rat liver, promoter II plays the major role in regulating the expression of ACC␤ gene. The transient transfection with promoter II-luciferase reporters elucidated that the region from ؊93 to ؊38 nucleotides is important for the responsiveness to sterol regulatory element-binding protein-1 (SREBP-1), which is known to be the principle mediator for the stimulation of gene transcriptions by insulin and diet. The Sp1-binding site (؊71 to ؊66) and neighboring two conserved SREs (؊62 to ؊44) play a critical role in the stimulation of ACC␤ gene expression by SREBP-1. In vivo chromatin immunoprecipitation assay revealed that SREBP-1 directly bound to ACC␤ promoter II in liver, and its binding was regulated by the diet. This study provides evidence that ACC␤ expression in liver is regulated at the transcriptional level by the direct interaction of SREBP-1 with promoter II. Acetyl-CoA carboxylase (ACC)1 catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, which is served not only as the substrate for fatty acid biosynthesis but also as a signal molecule for metabolic control of fatty acid ␤-oxidation in skeletal muscle and insulin secretion in pancreatic ␤ cells (1). Two isoforms of ACC have been identified (ACC␣ and ACC␤). These two isoforms are encoded by the separate genes and display distinct tissue distribution. The ␣ isoform of ACC (also called ACC1, 265 kDa) is mainly distributed in liver and adipose tissue, where lipogenesis is active. In contrast, the ␤ isoform of ACC (also called as ACC2, 275 kDa) is the predominant carboxylase in skeletal muscle and heart, where fatty acid ␤-oxidation serves as the main energy source (2). ACC␤ shows considerable homology to ACC␣ except the additional NH 2 -terminal portion, comprised of about 200 amino acids, which is known to direct ACC␤ to the outer membrane of mitochondria (3, 4). The level of malonyl-CoA generated by ACC␤ around mitochondria functions as the important factor in regulating mitochondrial fatty acid ␤-oxidation through inhibition of carnitine palmitoyl-CoA transferase I. The activities of ACC␤ in skeletal muscle are mainly regulated by phosphorylation and dephosphorylation but not by changes of enzyme contents (5-8). For example, sympathetic nerve stimulation or exercise increases the phosphorylation of ACC␤, resulting in the inhibition of ACC␤ activities and the increase of fatty acid oxidation (7)(8)(9)(10)(11).ACC␤ is also expressed in liver and HepG2 cells (4, 12). Oxidation of fatty acid also occurs actively in liver, but its regulation is different from that in skeletal muscle. In liver, fatty acid oxidation is increa...

Activation of liver X receptors promotes lipid accumulation but does not alter insulin action in human skeletal muscle cells

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Sterol Regulatory Element-Binding Protein-1 Mediates the Effect of Insulin on Hexokinase II Gene Expression in Human Muscle Cells

“…This likely reflected limitations in the quantitative aspect of the ChIP method. Indeed, clear differences in the level of the interaction are generally observed in hit-andmiss situations (24,25). Under our experimental conditions, SREBP-1c was already present in the nucleus of the muscle cells (Fig.…”

Hormonal Regulation of Acetyl-CoA Carboxylase Isoenzyme Gene Transcription

“…However, the effects of insulin and glucocorticoid, the two major regulatory factors of lipogenesis, on the promoter-specific transcriptional regulation of ACC1 and ACC2 gene are not clarified yet. Furthermore, the roles of representative insulin and/or carbohydrate-related transcription factors, such as sterol response element binding protein 1c (SReBP1c), liver X receptor α and β (LXRα/β), and carbohydrate response element binding protein (ChReBP), in the regulation of each promoter remain to be elucidated [13][14][15][16].…”