E4orf1: a novel ligand that improves glucose disposal in cell culture.

Reducing dietary fat intake and excess adiposity, the cornerstones of behavioral treatment of insulin resistance (IR), are marginally successful over the long term. Ad36, a human adenovirus, offers a template to improve IR, independent of dietary fat intake or adiposity. Ad36 increases cellular gluc...

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Autores principales:	Emily J Dhurandhar, Olga Dubuisson, Nazar Mashtalir, Rashmi Krishnapuram, Vijay Hegde, Nikhil V Dhurandhar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/35f6e4f688654ac599ce1b08ad07f0ef
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spelling	oai:doaj.org-article:35f6e4f688654ac599ce1b08ad07f0ef2021-11-18T06:47:29ZE4orf1: a novel ligand that improves glucose disposal in cell culture.1932-620310.1371/journal.pone.0023394https://doaj.org/article/35f6e4f688654ac599ce1b08ad07f0ef2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21886789/?tool=EBIhttps://doaj.org/toc/1932-6203Reducing dietary fat intake and excess adiposity, the cornerstones of behavioral treatment of insulin resistance (IR), are marginally successful over the long term. Ad36, a human adenovirus, offers a template to improve IR, independent of dietary fat intake or adiposity. Ad36 increases cellular glucose uptake via a Ras-mediated activation of phosphatidyl inositol 3-kinase(PI3K), and improves hyperglycemia in mice, despite a high-fat diet and without reducing adiposity. Ex-vivo studies suggest that Ad36 improves hyperglycemia in mice by increasing glucose uptake by adipose tissue and skeletal muscle, and by reducing hepatic glucose output. It is impractical to use Ad36 for therapeutic action. Instead, we investigated if the E4orf1 protein of Ad36, mediates its anti-hyperglycemic action. Such a candidate protein may offer an attractive template for therapeutic development. Experiment-1 determined that Ad36 'requires' E4orf1 protein to up-regulate cellular glucose uptake. Ad36 significantly increased glucose uptake in 3T3-L1 preadipocytes, which was abrogated by knocking down E4orf1 with siRNA. Experiment-2 identified E4orf1 as 'sufficient' to up-regulate glucose uptake. 3T3-L1 cells that inducibly express E4orf1, increased glucose uptake in an induction-dependent manner, compared to null vector control cells. E4orf1 up-regulated PI3K pathway and increased abundance of Ras--the obligatory molecule in Ad36-induced glucose uptake. Experiment-3: Signaling studies of cells transiently transfected with E4orf1 or a null vector, revealed that E4orf1 may activate Ras/PI3K pathway by binding to Drosophila discs-large (Dlg1) protein. E4orf1 activated total Ras and, particularly the H-Ras isoform. By mutating the PDZ domain binding motif (PBM) of E4orf1, Experiment-4 showed that E4orf1 requires its PBM to increase Ras activation or glucose uptake. Experiment-5: In-vitro, a transient transfection by E4orf1 significantly increased glucose uptake in preadipocytes, adipocytes, or myoblasts, and reduced glucose output by hepatocytes. Thus, the highly attractive anti-hyperglycemic effect of Ad36 is mirrored by E4orf1 protein, which may offer a novel ligand to develop anti-hyperglycemic drugs.Emily J DhurandharOlga DubuissonNazar MashtalirRashmi KrishnapuramVijay HegdeNikhil V DhurandharPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23394 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emily J Dhurandhar Olga Dubuisson Nazar Mashtalir Rashmi Krishnapuram Vijay Hegde Nikhil V Dhurandhar E4orf1: a novel ligand that improves glucose disposal in cell culture.
description	Reducing dietary fat intake and excess adiposity, the cornerstones of behavioral treatment of insulin resistance (IR), are marginally successful over the long term. Ad36, a human adenovirus, offers a template to improve IR, independent of dietary fat intake or adiposity. Ad36 increases cellular glucose uptake via a Ras-mediated activation of phosphatidyl inositol 3-kinase(PI3K), and improves hyperglycemia in mice, despite a high-fat diet and without reducing adiposity. Ex-vivo studies suggest that Ad36 improves hyperglycemia in mice by increasing glucose uptake by adipose tissue and skeletal muscle, and by reducing hepatic glucose output. It is impractical to use Ad36 for therapeutic action. Instead, we investigated if the E4orf1 protein of Ad36, mediates its anti-hyperglycemic action. Such a candidate protein may offer an attractive template for therapeutic development. Experiment-1 determined that Ad36 'requires' E4orf1 protein to up-regulate cellular glucose uptake. Ad36 significantly increased glucose uptake in 3T3-L1 preadipocytes, which was abrogated by knocking down E4orf1 with siRNA. Experiment-2 identified E4orf1 as 'sufficient' to up-regulate glucose uptake. 3T3-L1 cells that inducibly express E4orf1, increased glucose uptake in an induction-dependent manner, compared to null vector control cells. E4orf1 up-regulated PI3K pathway and increased abundance of Ras--the obligatory molecule in Ad36-induced glucose uptake. Experiment-3: Signaling studies of cells transiently transfected with E4orf1 or a null vector, revealed that E4orf1 may activate Ras/PI3K pathway by binding to Drosophila discs-large (Dlg1) protein. E4orf1 activated total Ras and, particularly the H-Ras isoform. By mutating the PDZ domain binding motif (PBM) of E4orf1, Experiment-4 showed that E4orf1 requires its PBM to increase Ras activation or glucose uptake. Experiment-5: In-vitro, a transient transfection by E4orf1 significantly increased glucose uptake in preadipocytes, adipocytes, or myoblasts, and reduced glucose output by hepatocytes. Thus, the highly attractive anti-hyperglycemic effect of Ad36 is mirrored by E4orf1 protein, which may offer a novel ligand to develop anti-hyperglycemic drugs.
format	article
author	Emily J Dhurandhar Olga Dubuisson Nazar Mashtalir Rashmi Krishnapuram Vijay Hegde Nikhil V Dhurandhar
author_facet	Emily J Dhurandhar Olga Dubuisson Nazar Mashtalir Rashmi Krishnapuram Vijay Hegde Nikhil V Dhurandhar
author_sort	Emily J Dhurandhar
title	E4orf1: a novel ligand that improves glucose disposal in cell culture.
title_short	E4orf1: a novel ligand that improves glucose disposal in cell culture.
title_full	E4orf1: a novel ligand that improves glucose disposal in cell culture.
title_fullStr	E4orf1: a novel ligand that improves glucose disposal in cell culture.
title_full_unstemmed	E4orf1: a novel ligand that improves glucose disposal in cell culture.
title_sort	e4orf1: a novel ligand that improves glucose disposal in cell culture.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/35f6e4f688654ac599ce1b08ad07f0ef
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E4orf1: a novel ligand that improves glucose disposal in cell culture.

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