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Phosphorus Overload Promotes Hepatic Lipolysis by Suppressing GSK3β-Dependent Phosphorylation of PPARα 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… Click to show full abstract

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 β (GSK3β) at serine 9 (S9) but inhibited the phosphorylation of GSK3α at tyrosine 279 (Y279), GSK3β at tyrosine 216 (Y216), and peroxisome proliferator-activated receptor α (PPARα) at serine 84 (S84) and threonine 265 (T265). Pi supplementation also upregulated PPARα protein expression and stimulated its transcriptional activity, thereby inducing lipolysis. Pi suppressed GSK3β activity and prevented GSK3β, but not GSK3α, from interacting with PPARα, which in turn alleviated PPARα phosphorylation. GSK3β-induced phosphorylation of PPARα was dependent on GSK3β S9 dephosphorylation rather than Y216 phosphorylation. Mechanistically, underphosphorylation of PPARα 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 GSK3β-PPARα pathway and highlighted the importance of S84 and T265 phosphorylation in PPARα action.

Keywords: phosphorus; lipolysis; gsk3; phosphorylation; phosphorylation ppar

Journal Title: Environmental science & technology
Year Published: 2023

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