Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia

Abstract

The rs780094 single nucleotide polymorphism (SNP; C/T) of glucokinase regulatory protein gene (GCKR) is a regulatory genetic variant that has been associated with lactate levels in the fasting state. However, the association of this locus with lactate during hyperglycemia, and the mechanisms underlying these associations remain unknown. We investigated the association of rs780094 with lactate levels in a frequently sampled oral glucose tolerance test in humans and evaluated the effect of increasing GCKR expression on lactate production in liver cells. The C allele of rs780094 was associated with lower lactate levels in fasting but increased lactate level during hyperglycemia independently of insulin levels. Increased expression of GKRP induced higher lactate level in HepG2 cells and in human primary hepatocytes (HPH) upon glucose stimulation by increasing the amount of GCK. Glucagon induced the expression of GCKR in HepG2 and HPH cells. Our results suggest that the association of rs780094 with lactate levels may involve differential GCKR expression between the carriers of the C and T alleles.

Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology

“…GCKR regulates de novo lipogenesis by modulating the influx of glucose into hepatocytes and consequently the flow of substrate for lipogenesis. Most data point to a common SNP (rs1260326), encoding for the P446L variant, as the causal variant underlying the association with fatty liver (58)(59)(60). This amino acid substitution impairs the ability of GCKR to inhibit glucokinase in response to fructose-6-phosphate, a response which represents a negative feedback loop controlling hepatic glucose uptake (58,60).…”

“…Most data point to a common SNP (rs1260326), encoding for the P446L variant, as the causal variant underlying the association with fatty liver (58)(59)(60). This amino acid substitution impairs the ability of GCKR to inhibit glucokinase in response to fructose-6-phosphate, a response which represents a negative feedback loop controlling hepatic glucose uptake (58,60). The functional consequences for subjects harboring the P446L GCKR variant include decreased circulating glucose and heightened insulin sensitivity, which might portend net benefit, but at the same time the P446L variant increases hepatic production of malonyl-CoA, which promotes hepatic triglyceride accumulation by serving as a substrate for de novo lipogenesis and by blocking fatty acid oxidation, thus promoting hepatic steatosis (59).…”

Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy?

“…The GCKR rs780094 polymorphism is significantly associated with CT-and histologically proven hepatic steatosis in GWAS (OR = 1.45, p = 2.59x10 −8 ) (Speliotes et al, 2011) and in metaanalysis of five studies (2,091 NAFLD cases and 3,003 controls) (OR: 1.25, 95% CI 1.14-1.36, p < 0.00001, I 2 = 0%) (Zain et al, 2015). This polymorphism is associated with higher expression of GCKR (Rodríguez et al, 2018), and with reduced risk of T2DM (Sparsø et al, 2008;Onuma et al, 2010). In patients with NAFLD the rs780094 C > T polymorphism is significantly associated with hepatic fibrosis stage > F1 (OR: 2.06, 95% CI 1.02-1.14, p = 0.0008) (Petta et al, 2014).…”

Genetic risk factors associated with NAFLD

“…The T risk allele of rs1260326 is associated with higher GCKR expression [39] . Unlike the wild-type GCKR protein, the GCKR P446L protein is not sustained by fructose-6-phosphate, resulting in enhanced hepatic uptake of glucose, glucokinase activity [40] , and de novo lipogenesis [41] .…”