Acetyl-CoA carboxylase-α: Gene structure-function relationships

ABSTRACT Acetyl-CoA carboxylase-α (ACC-α) is a key enzyme in the regulation of fatty acid synthesis and is subject to both acute control, via reversible phosphorylation, and chronic control that results in the regulation of synthesis of the enzyme. The gene for ACC-α is expressed ubiquitously, but expression is highest in lipogenic tissues: adipose, liver, and lactating mammary gland. These tissues demonstrate a metabolic adaptation to changing physiological demands; for example, during lactation fatty acid synthesis in adipose tissue is markedly repressed, resulting in the partitioning of lipogenic precursors to the mammary gland. Lipogenic tissues can also exhibit dysfunctions that result in excess fat deposition in farm animals and obesity in humans. Transcription of the ACC-α gene is initiated from multiple promoters in a tissue-specific fashion. Promoter II (PII) transcripts are present in all tissues, whereas promoter I (PI) transcripts are principally restricted to adipose tissue. We have also identified an additional promoter (PIII) that is also expressed in a tissue-restricted manner. All three promoters are modulated by the physiological state of an animal, suggesting that each promoter possesses enhancer domains that are targets for cell-specific signaling pathways and act in concert with the basal transcriptional machinery to regulate expression of the gene. For example, expression of the ACC-α gene is increased in mammary gland during lactation concomitant with the increase in the rate of fatty acid synthesis; in sheep this arises through induction of both PII and PIII promoter activities. Conversely, the ACC-α gene is repressed in sheep adipose tissue during lactation, and this occurs primarily through inactivation of PI, although PII activity is also repressed. This may arise in part from a change in sensitivity of the tissue to insulin. Analysis of the structure and function of the various promoters of ACC-α is presented with a view to determining the molecular basis of the modulation of expression of this gene in lipogenic tissues.

Implications

A major feature of the metabolic adaptation that results in transfer of lipogenic capacity through repression and activation of the acetyl-CoA carboxylase-α (ACC-α) gene in adipose tissue and mammary gland, respectively, during lactation is that it is largely promoter (P)-specific. The PI is potently repressed in adipocytes, PII activity is only modulated slightly, and corresponding changes in mammary gland involve modest induction of PII and potent induction of PIII. Transcription from PI and PIII, respectively, seem necessary for the differentiative function of the adipocyte and mammary epithelial cell, respectively. The ACC-α transcript heterogeneity may be involved in the segregation of metabolic pathways into discrete cellular compartments, or in the case of the E5A transcript, in which the protein sequence is altered, an effect on enzyme kinetics may also be inferred. Further research will be required to work out the molecular details of this speculation.

Key Words: Adipose Tissue, Insulin, Mammary Glands

© 2001, by the American Society of Animal Science. All rights reserved.

J. Anim. Sci. 2001. 79:E136-E143