PHLPPs: Emerging players in metabolic disorders

• Published in: Drug discovery today 2022-10, Vol.27 (10), p.103317-103317, Article 103317
• Main Authors: Balamurugan, Keerthana, Chandra, Kanika, Sai Latha, S., Swathi, M., Joshi, Manjunath B., Misra, Parimal, Parsa, Kishore V.L.
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases; Atherosclerosis; Cardiovascular dysfunction; Glucose; Humans; Insulin Resistance; Mechanistic Target of Rapamycin Complex 1; Nuclear Proteins - metabolism; PHLPP1; PHLPP2; Phosphatidylinositol 3-Kinases; Phosphoprotein Phosphatases - metabolism; PPAR alpha; Proto-Oncogene Proteins c-akt - metabolism; TOR Serine-Threonine Kinases; Type 2 diabetes
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2022.07.002

[Display omitted] •PHLPP1 signalling is involved in diabetes mellitus and cardiovascular diseases.•PHLPP1/2 deficiency is cardio-protective and athero-protective.•PHLPPs suppression rescue HFD-induced diabetes and fatty liver in mice.•Diabetic and CVD patients show higher PHLPP1/2 levels.•PHLPP1/2 inhibition hold potential significance in treating metabolic disorders. That reversible protein phosphorylation by kinases and phosphatases occurs in metabolic disorders is well known. Various studies have revealed that a multi-faceted and tightly regulated phosphatase, pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP)-1/2 displays robust effects in cardioprotection, ischaemia/reperfusion (I/R), and vascular remodelling. PHLPP1 promotes foamy macrophage development through ChREBP/AMPK-dependent pathways. Adipocyte-specific loss of PHLPP2 reduces adiposity, improves glucose tolerance,and attenuates fatty liver via the PHLPP2–HSL–PPARα axis. Discoveries of PHLPP1-mediated insulin resistance and pancreatic β cell death via the PHLPP1/2–Mst1–mTORC1 triangular loop have shed light on its significance in diabetology. PHLPP1 downregulation attenuates diabetic cardiomyopathy (DCM) by restoring PI3K–Akt–mTOR signalling. In this review, we summarise the functional role of, and cellular signalling mediated by, PHLPPs in metabolic tissues and discuss their potential as therapeutic targets.