TY - JOUR
T1 - PHLPPs
T2 - Emerging players in metabolic disorders
AU - Balamurugan, Keerthana
AU - Chandra, Kanika
AU - Sai Latha, S.
AU - Swathi, M.
AU - Joshi, Manjunath B.
AU - Misra, Parimal
AU - Parsa, Kishore V.L.
N1 - Funding Information:
K.V.L.P. appreciates the thoughtful insights from his lab members. The authors are also grateful to Gangireddy Sujeevan Reddy for his help with Chemdraw to draw PHLPP inhibitors. Graphical abstract and Figs. 1C, 2–4 were created with BioRender (BioRender.com). The research work in K.V.L.P.’s lab is funded by grant from the Scientific & Research Engineering Board, India (CRG/2019/002570) and Department of Biotechnology, India (BT/PR27445/ MED/30/1962/2018). The funders had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.drudis.2022.07.002
DO - 10.1016/j.drudis.2022.07.002
M3 - Review article
C2 - 35835313
AN - SCOPUS:85134764396
SN - 1359-6446
VL - 27
JO - Drug Discovery Today
JF - Drug Discovery Today
IS - 10
M1 - 103317
ER -
