Acetyl-CoA carboxylase β expression mediated by MyoD and muscle regulatory factor 4 is differentially affected by retinoic acid receptor and retinoid X receptor

Abstract

Mammals have two major isoforms of acetyl-CoA carboxyase (ACC). The 275 kDa β-form (ACCβ) is predominantly in heart and skeletal muscle while the 265 kDa α-form (ACCα) is the major isoform in lipogenic tissues such as liver and adipose tissue. ACCα is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine palmitoyl-CoA transferase-1 (CPT-1), which is a rate-limiting enzyme of fatty acid oxidation in mitochondria. Previously, it was reported that MyoD and other muscle regulating factors (MRFs) up-regulate the expression of ACCβ by interactions between these factors and several cis-elements of ACCβ promoter. We described here that ACCβ expression mediated by MRFs is regulated by retinoic acids. Endogenous expression of ACCβ in differentiated H9C2 myotube was significantly increased by retinoic acid treatment. However, on transient transfection assay in H9C2 myoblast, ACCβ promoter activity was suppressed by RXRα and more severely by RARα. These effects on ACCβ expression in myoblasts and myotubes by RXRα and RARα seem to be mediated by their interactions with MRFs because no consensus sequence for RXRα and RARα has been found in ACCβ promoter and retinoic acid receptors did not affect this promoter activities by itself. In transient transfection in NIH3T3 fibroblast, the activation of ACCβ promoter by MyoD, main MRF in myoblast, was significantly suppressed by RARα and to a less extent by RXRα while the RXRα drastically augmented the activation by MRF4, major MRF in myotube. These results explained that retinoic acids differentially affected the action of MRFs according to their types and RXRα specially elevates the expression of muscle specific genes by stimulating the action of MRF4.