Figure 5 -. Many GCKR Associated Metabolic Traits Lie Downstream of Hepatic NADH Reductive Stress.

(a) GWAS studies have linked many traits to GCKR variation. The current study raises the hypothesis that some of these are mediated by variation in hepatic NADH/NAD⁺ (b) Shown are 51 such traits that we could measure using the EtOH/LbNOX in vivo system in Figure 3a, with the analyte Z score for each condition relative to Luc+H₂0, whether the measured analyte fulfilled our criteria fo “NADH/NAD⁺ sensitivity” (see Material and Methods) and if so its direction, along with the observed direction of effect from the P446L risk haplotype in published studies (Supplementary Table 1). Selected data are shown for (c) plasma glucose, (d) total plasma triglycerides, (e) plasma serine, and (f) plasma FGF21. (g) Proposed model, where circulating αHB is a biomarker of elevated cytosolic free hepatic NADH/NAD⁺, a latent metabolic parameter that is influenced by genetic and environmental factors and serves as an effector of different metabolic traits. Data are mean ± s.e.m from n=7–10 mice per group. Nominal p values were determined using two-sided Student’s T tests used for “NADH/NAD⁺” sensitivity calculations. TAG= triacylglycerol; DAG= diacylglycerol; MAG= monoacylglycerol; PE = phosphatidylethanolamine; PC phosphatidylcholine; LPE = lysophosphatidylethanolamine; LPC lysophophatidylcholine; PC-PL phosphatidychloine plasmalogen; γGT γ−glutamylthreonine; GGT gamma-glutamyltransferase; CRP C-reactive protein; NAT N-acetyltrytophan.