ArticleMolecular metabolism2023
The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326.
Article in Molecular metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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12 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease.Frontiers in endocrinology · 2023Pooled it
- Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.Molecular metabolism · 2026Article
- A dish-to-biobank framework links β-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes.bioRxiv : the preprint server for biology · 2026Article
- Glucokinase activity suppresses hepatic cholesterol synthesis and triglyceride accumulation: A new model for the effects of the GKRP P466L common human variant.bioRxiv : the preprint server for biology · 2026Article
- The U-shaped association between the metabolic score for insulin resistance and incident gallstone disease: a population-based cohort study.Frontiers in endocrinology · 2026Article
- Molecular mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD): functional analysis of glucose and fructose metabolism pathways.Clinical science (London, England : 1979) · 2025Review
- Association of non-alcoholic fatty liver polygenic risk scores with the incident and progressive non-alcoholic fatty liver disease in Chinese population.Genes & nutrition · 2025Article
- Significant Association Between Glucokinase Regulatory Protein Variants and Genetic and Metabolic Diseases.Current issues in molecular biology · 2025Review
- Gene-based therapies for steatotic liver disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Glucokinase Regulatory Protein (GCKR) Links Metabolic Reprogramming With Immune Exclusion: Insights From a Pan-Cancer Analysis and Gastric Cancer Validation.Human mutation · 2025Article
- Interplay of Mediterranean-diet adherence, genetic factors, and metabolic dysfunction-associated steatotic liver disease risk in Korea.Journal of translational medicine · 2024Article
- Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD.Frontiers in endocrinology · 2023Review
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Authors and funding
12 authors at 6 institutions in 4 countries.
Funding
Abstract
objectivesThe 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.
methodsGKRP-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.
results1. 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.
conclusionsMouse 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.
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