Peroxisome proliferator-activated receptor γ1 and γ2 isoforms alter lipogenic gene networks in goat mammary epithelial cells to different extents

Abstract

In nonruminants, the alternative splicing of peroxisome proliferator-activated receptor γ (PPARG) generates PPARG1 and PPARG2 isoforms. Although transcriptional control differences between isoforms have been reported in human adipose tissue, their roles in ruminant mammary cells are not well known. To assess which of these isoforms is more closely associated with the regulation of mammary lipogenic pathways, their tissue distribution was analyzed and the expression of key genes regulating lipogenic gene networks was measured after overexpression of the 2 isoforms in goat mammary epithelial cells (GMEC). The expression of PPARG2 was markedly greater in adipose tissue, whereas PPARG1 is the main isoform in goat mammary tissue (ratio of PPARG1:PPARG2 was close to 37:1). As was reported in previous work, PPARG1 upregulated the transcription regulators SREBF1 and PPARG and the lipogenic genes FASN, ACACA, and SCD. Along with a tendency for greater expression of AGPAT6, DGAT1, and PLIN2, these data suggest that PPARG1 is the isoform controlling lipogenesis in mammary cells. Addition of the PPARG ligand rosiglitazone (ROSI) to GMEC overexpressing both isoforms upregulated the expression of LPL and CD36, which help control uptake of long-chain fatty acids into mammary cells. Other responses to ROSI addition to GMEC overexpressing PPARG1 and PPARG2 included upregulation of AGPAT6, DGAT1, INSIG1, SREBF1, and NR1H3. Although the data suggest that both PPARG1 and PPARG2 could affect mammary lipogenesis via control of gene expression when stimulated (e.g., by ROSI), the fact that PPARG1 is more abundant in mammary tissue and that its overexpression alone upregulated key lipogenic gene networks suggest that it is the more important isoform in goat mammary cells.

Association of the PPARγ2 Pro12Ala polymorphism with increased risk of cardiovascular diseases

“…The two isoforms of PPAR γ (γ1 and γ2) differ at their N-terminus, and the PPARγ2 isoform is specific to adipose tissue (Shi et al, 2014). The most common genetic polymorphism in the human PPARγ2 gene is a cytosine-guanine exchange in exon B (codon 12), which results in a Pro12Ala substitution in the protein, and carriers of Ala12, which is a common variant, have high fatty acids accumulation in adipose tissue (Xu et al, 2013;Fernández-Rodríguez et al, 2014).…”

The effect of long term under- and over-feeding on the expression of genes related to lipid metabolism in the mammary tissue of goats

“…These FA maybe further desaturated by the stearoyl-Co A desaturase 1 (SCD1) but not elongated. In addition, the process of the FA biosynthesis is controlled also by transcription factors such as the isoform c of the sterol regulatory element binding protein-1 (SREBP-1c), which is involved in triglycerides synthesis (Rudolph et al, 2010;Ma and Corl, 2012;Xu et al, 2012), and the isoform G2 of the proliferator activated receptor G (PPARG2), which alters lipogenic genes networks in goats mammary epithelial cells (Shi et al, 2013;2014). Further to that, recent evidence also confirms the involvement of hormone sensitive lipase (HSL) gene on lipid metabolism in goats mammary epithelial cells (Lin et al, 2013).…”

Transcriptome-Wide Analysis Reveals the Role of PPARγControlling the Lipid Metabolism in Goat Mammary Epithelial Cells

“…Therefore, understanding the mechanisms for altering the milk fatty acid composition of goat milk may lead to further improvements in nutritional value. Recent evidence indicates that milk fat biosynthesis is regulated by key transcription factors including peroxisome proliferator-activated receptor γ ( PPARG ) [2, 3]. …”