Phosphorus Overload Promotes Hepatic Lipolysis by Suppressing GSK3 beta-Dependent Phosphorylation of PPAR alpha at Ser84 and Thr265 in a Freshwater Teleost

Excessive phosphorus (Pi) contributes to eutrophication in an aquatic environment, which threatens human and fish health. However, the mechanisms by which Pi overload influences aquatic animals remain largely unexplored. In the present study, Pi supplementation increased the Pi content, inhibited lipid accumulation and lipogenesis, and stimulated lipolysis in the liver. Pi supplementation increased the phosphorylation of glycogen synthase kinase-3 beta (GSK3 beta) at serine 9 (S9) but inhibited the phosphorylation of GSK3 alpha at tyrosine 279 (Y279), GSK3 beta at tyrosine 216 (Y216), and peroxisome proliferator-activated receptor alpha (PPAR alpha) at serine 84 (S84) and threonine 265 (T265). Pi supplementation also upregulated PPAR alpha protein expression and stimulated its transcriptional activity, thereby inducing lipolysis. Pi suppressed GSK3 beta activity and prevented GSK3 beta, but not GSK3 alpha, from interacting with PPAR alpha, which in turn alleviated PPAR alpha phosphorylation. GSK3 beta-induced phosphorylation of PPAR alpha was dependent on GSK3 beta S9 dephosphorylation rather than Y216 phosphorylation. Mechanistically, underphosphorylation of PPAR alpha mediated Pi-induced lipid degradation through transcriptionally activating adipose triglyceride lipase (atgl) and very long-chain-specific acyl-CoA dehydrogenase (acadvl). Collectively, our findings uncovered a new mechanism by which Pi facilitates lipolysis via the GSK3 beta-PPAR alpha pathway and highlighted the importance of S84 and T265 phosphorylation in PPAR alpha action.