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

Lookup NU author(s): Dr Brian FordORCiD, Dr Shruti Chachra, Katrina Rodgers, Tabassum Moonira, Dr Ziad Al-Oanzi, Professor Quentin AnsteeORCiD, Professor Helen ReevesORCiD, Dr Dina Tiniakos, Emerita Professor Loranne Agius

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

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.

Publication metadata

Author(s): Ford BE, Chachra SS, Rodgers K, Moonira T, Al-Oanzi ZH, Anstee QM, Reeves HL, Schattenberg JM, Fairclough RJ, Smith DM, Tiniakos D, Agius L

Publication type: Article

Publication status: Published

Journal: Molecular Metabolism

Year: 2023

Volume: 72

Print publication date: 21/04/2023

Online publication date: 07/04/2023

Acceptance date: 04/04/2023

Date deposited: 21/04/2023

ISSN (electronic): 2212-8778

Publisher: Elsevier

URL: https://doi.org/10.1016/j.molmet.2023.101722

DOI: 10.1016/j.molmet.2023.101722

PubMed id: 37031802

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