Fine metabolic regulation in ruminants via nutrient-gene interactions: saturated long-chain fatty acids increase expression of genes involved in lipid metabolism and immune response partly through PPAR-α activation

Madin-Darby Bovine Kidney cells cultured with 150 mu M of Wy-14 643 (WY, PPAR alpha agonist) or twelve long-chain fatty acids (LCFA; 16: 0, 18:0, cis-9-18: 1, trans-10-18 : 1, trans-11-18: 1, 18: 2n-6, 18: 3n-3, cis-9, trans-11-18 : 2, trans-10, cis-12-18:2, 20 : 0, 20 : 5n-3 and 22: 6n-3) were used to uncover PPAR-alpha target genes and determine the effects of LCFA on expression of thirty genes with key functions in lipid metabolism and inflammation. Among fifteen known PPAR-alpha targets in non-ruminants, ten had greater expression with WY, suggesting that they are bovine PPAR-alpha targets. The expression of SPP1 and LPIN3 was increased by WY, with no evidence of a similar effect in the published literature, suggesting that both represent bovine-specific PPAR-alpha targets. We observed the strongest effect on the expression of PPAR-alpha targets with 16:0, 18:0 and 20: 5n-3. When considering the overall effect on expression of the thirty selected genes 20:5n-3, 16:0 and 18:0 had the greatest effect followed by 20:0 and c9t11-18:2. Gene network analysis indicated an overall increase in lipid metabolism by WY and all LCFA with a central role of PPAR-a but also additional putative transcription factors. A greater increase in the expression of inflammatory genes was observed with 16: 0 and 18: 0. Among LCFA, 20: 5n-3, 16:0 and 18:0 were the most potent PPAR-alpha agonists. They also affected the expression of non-PPAR-alpha targets, eliciting an overall increase in the expression of genes related to lipid metabolism, signalling and inflammatory response. Data appear to highlight a teleological evolutionary adaptation of PPAR in ruminants to cope with the greater availability of saturated rather than unsaturated LCFA.