The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326.

Autor:	Ford BE; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Chachra SS; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Rodgers K; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Moonira T; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Al-Oanzi ZH; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Jouf University, Clinical Laboratory Science, Sakaka, Saudi Arabia., Anstee QM; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK., Reeves HL; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK., Schattenberg JM; Metabolic Liver Research Programm, Department of Medicine, University Hospital Mainz, Mainz, Germany., Fairclough RJ; Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Smith DM; Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Tiniakos D; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK; Dept of Pathology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Agius L; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Electronic address: loranne.agius@newcastle.ac.uk.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2023 Jun; Vol. 72, pp. 101722. Date of Electronic Publication: 2023 Apr 07.
DOI:	10.1016/j.molmet.2023.101722
Abstrakt:	Objectives: The Glucokinase Regulatory Protein GKRP, encoded by GCKR, enables acute regulation of liver glucokinase to support metabolic demand. The common human GCKR rs1260326:Pro446 > Leu variant within a large linkage disequilibrium region associates with pleiotropic traits including lower Type 2 diabetes risk and raised blood triglycerides and cholesterol. Whether the GCKR-P446 > L substitution is causal to the raised lipids is unknown. We determined whether mouse GKRP phenocopies the human GKRP:P446 > L substitution and studied a GKRP:P446L knockin mouse to identify physiological consequences to P446 > L. Methods: GKRP-deficient hepatocytes were transfected with adenoviral vectors for human or mouse GKRP:446 P or 446 L for cellular comprehensive analysis including transcriptomics consequent to P446 > L. Physiological traits in the diet-challenged P446L mouse were compared with pleiotropic associations at the human rs1260326 locus. Transcriptomics was compared in P446L mouse liver with hepatocytes overexpressing glucokinase or GKRP:446 P/L. Results: 1. P446 > L substitution in mouse or human GKRP similarly compromises protein expressivity of GKRP:446 L, nuclear sequestration of glucokinase and counter-regulation of gene expression. 2. The P446L knockin mouse has lower liver glucokinase and GKRP protein similar to human liver homozygous for rs1260326-446 L. 3. The diet-challenged P446L mouse has lower blood glucose, raised blood cholesterol and altered hepatic cholesterol homeostasis consistent with relative glucokinase-to-GKRP excess, but not raised blood triglycerides. Conclusions: Mouse GKRP phenocopies the human GKRP:P446 > L substitution despite the higher affinity for glucokinase of human GKRP. The diet-challenged P446L mouse replicates several traits found in association with the rs1260326 locus on chromosome 2 including raised blood cholesterol, lower blood glucose and lower liver glucokinase and GKRP protein but not raised blood triglycerides. (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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