Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ)*

Terry D. Hinds, Lance A. Stechschulte, Harrison A. Cash, Donald Whisler, Ananya Banerjee, Weidong Yong, Saja S. Khuder, Meenakshi K. Kaw, Weinian Shou, Sonia M. Najjar, Edwin R. Sanchez

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) regulate adipogenesis by controlling the balance between lipolysis and lipogenesis. Here, we show that protein phosphatase 5 (PP5), a nuclear receptor cochaperone, reciprocally modulates the lipometabolic activities of GRα and PPARγ. Wild-type and PP5-deficient (KO) mouse embryonic fibroblast cells were used to show binding of PP5 to both GRα and PPARγ. In response to adipogenic stimuli, PP5-KO mouse embryonic fibroblast cells showed almost no lipid accumulation with reduced expression of adipogenic markers (aP2, CD36, and perilipin) and low fatty-acid synthase enzymatic activity. This was completely reversed following reintroduction of PP5. Loss of PP5 increased phosphorylation of GRα at serines 212 and 234 and elevated dexamethasone-induced activity at prolipolytic genes. In contrast, PPARγ in PP5-KO cells was hyperphosphorylated at serine 112 but had reduced rosiglitazone-induced activity at lipogenic genes. Expression of the S112A mutant rescued PPARγ transcriptional activity and lipid accumulation in PP5-KO cells pointing to Ser-112 as an important residue of PP5 action. This work identifies PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium and as a potential target in the treatment of obesity.

Original languageEnglish (US)
Pages (from-to)42911-42922
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number50
DOIs
StatePublished - Dec 16 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Hinds, T. D., Stechschulte, L. A., Cash, H. A., Whisler, D., Banerjee, A., Yong, W., Khuder, S. S., Kaw, M. K., Shou, W., Najjar, S. M., & Sanchez, E. R. (2011). Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ)*. Journal of Biological Chemistry, 286(50), 42911-42922. https://doi.org/10.1074/jbc.M111.311662