Structure and regulation of acetyl-CoA carboxylase genes of metazoa.

Acetyl-CoA carboxylase (ACC) plays a fundamental role in fatty acid metabolism. The reaction product, malonyl-CoA, is both an intermediate in the de novo synthesis of long-chain fatty acids and also a substrate for distinct fatty acyl-CoA elongation enzymes. In metazoans, which have evolved energy storage tissues to fuel locomotion and to survive periods of starvation, energy charge sensing at the level of the individual cell plays a role in fuel selection and metabolic orchestration between tissues.

Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland.

We have developed a mouse model of diet-induced obesity that shows numerous abnormalities relating to mammary gland function. Animals ate approximately 40% more calories when offered a high-fat diet and gained weight at three times the rate of controls. They exhibited reduced conception rates, increased peripartum pup mortality, and impaired lactogenesis.

Asymmetric expression of transcripts derived from the shared promoter between the divergently oriented ACACA and TADA2L genes.

The mammalian gene (ACACA) encoding acetyl-CoA carboxylase-alpha, a key regulatory enzyme of fatty acid synthesis, is transcribed from multiple promoters. We have delineated the 5' boundary of ACACA in four species (human, mouse, rat, and ovine). The 5' end of ACACA is located within a 600- to 700-bp CpG island encompassing a bidirectional promoter shared with the divergently oriented TADA2L, which encodes a component of chromatin-modifying complexes.

Characterisation of an N-terminal variant of acetyl-CoA carboxylase-alpha: expression in human tissues and evolutionary aspects.

mRNA encoding a variant acetyl-CoA carboxylase (ACC)-alpha isozyme, transcribed from a downstream promoter, PIII, was detected in human tissues. Such exon 5A-containing transcripts (E5A-mRNA) encode ACC-alpha with a distinct N-terminus, with 15/17 residues identical to those encoded by the ovine mRNA. In the current study we used antisera directed against the E5A N-terminus to verify that ovine E5A translates are present in tissues consistent with the distribution of E5A-mRNA.

Induction of transcripts derived from promoter III of the acetyl-CoA carboxylase-alpha gene in mammary gland is associated with recruitment of SREBP-1 to a region of the proximal promoter defined by a DNase I hypersensitive site.

ACC-alpha (acetyl-CoA carboxylase-alpha), a key regulator of fatty-acid metabolism, is encoded by mRNAs transcribed from three promoters, PI, PII and PIII, in the ovine genome. Enhanced expression of transcripts encoded by PIII in mammary gland during lactation is associated with alterations in chromatin structure that result in the detection of two DNase I hypersensitive sites, upstream of the start site. The most proximal site, located between -190 and -10, is characterized by the presence of an inverted-CCAAT box, C2 at -167, and E-boxes, E1 and E2, at -151 and -46.

Localization of messenger RNAs encoding enzymes associated with malonyl-CoA metabolism in mouse brain.

Malonyl-CoA acts a fuel sensor in the pancreas, liver and muscle. Similarly, malonyl-CoA is implicated in satiety regulation in the brain. Expression of genes encoding enzymes implicated in regulation of malonyl-CoA levels was examined in murine brain.

Growth hormone, acting in part through the insulin-like growth factor axis, rescues developmental, but not metabolic, activity in the mammary gland of mice expressing a single allele of the prolactin receptor.

The heterozygous prolactin (PRL) receptor (PRLR(+/-)) mouse fails to develop a fully functional mammary gland at the end of the first pregnancy and shows markedly impaired lobuloalveolar development and milk secretion in young females. PRL and GH, acting through the IGF system, have interactive effects to enhance epithelial cell survival. Thus, we propose that a reduction in the expression of the PRLR may lead to increased IGFBP-5 expression (proapoptotic) and that GH may rescue mammary development by increasing IGF-I, an important mitogen and survival factor for the mammary epithelium.

Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice.

We have previously demonstrated that IGFBP-5 production by mammary epithelial cells increases dramatically during involution of the mammary gland. To demonstrate a causal relationship between IGFBP-5 and cell death we created transgenic mice expressing IGFBP-5 in the mammary gland using a mammary-specific promoter, beta-lactoglobulin. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy.