Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene

Abstract

This study reports for the first time rates of DNL in obese adolescents and suggests that the GCKR rs1260326 gene variant, which is associated with greater glycolysis, increases hepatic DNL. These data highlight the role of glycolytic carbon flux in liver lipid synthesis and hypertriglyceridemia in these youngsters.

From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease

“…The higher concentration of large VLDL results in a high concentration in plasma of very small LDL, which in turn are a major contributor to the atherosclerotic plaque[7], and their accumulation within the plaque would ultimately lead to ischemic events. NAFLD per se , in fact, is a hyperlipidemic state in which adipose tissue insulin resistance[10] and enhanced hepatic de novo lipogenesis[11] lead to an abnormal accumulation of fat in the liver, turning the hepatocytes in a fat producing factory.…”

“…To explain this observation several pathogenic mechanisms have been hypothesized, including the role of the liver as a generator of circulating mediators that could be involved in the cardiac remodeling[3,11,16,17]. In fact, the presence of a low-grade inflammatory state in patients obese patients with NAFLD and insulin resistance contributes to release of several cytokines and adipokines ( e.g ., IL-6, TNF-alpha, visfatin, FGF-21, adiponectin, resistin, leptin) that amplify this condition and worsen the metabolic phenotype[3,11,17].…”

“…In fact, the presence of a low-grade inflammatory state in patients obese patients with NAFLD and insulin resistance contributes to release of several cytokines and adipokines ( e.g ., IL-6, TNF-alpha, visfatin, FGF-21, adiponectin, resistin, leptin) that amplify this condition and worsen the metabolic phenotype[3,11,17]. Whether the trigger for this condition, usually refereed to as “sterile inflammation”, is NAFLD or insulin resistance per se is unclear, but a large body of evidence suggests that inflammatory cytokines may be the link among fatty liver, insulin resistance and myocardial changes[3,17].…”

Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men

“…Fasting and postprandial hepatic DNL was assessed doi: 10.1210/jc.2015-2649 press.endocrine.org/journal/jcem based on the incorporation of deuterium from 2 H 2 O in plasma water (Finnigan GasBench-II, ThermoFisher Scientific, UK) into VLDL-TG palmitate using GC-MS with monitoring ions with mass-to-charge ratios (m/z) of 270 (Mϩ0) and 271 (Mϩ1) (26). Absolute DNL was calculated by multiplying %DNL and the concentration of TG in VLDL (27). We assessed the synthesis of newly made palmitate into VLDL-TG but for simplicity, we will refer to this as 'DNL'.…”

A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies

“…In statistical terms, this biological mechanism would be reflected by an interaction between indices of glucose metabolism and rs1260326. Indeed, individuals carrying the rs1260326 minor T allele are characterized by increased de novo lipogenesis when compared with homozygous carriers of the C allele (34). Finally, the negative interaction between the rs1260326 minor T allele and indices of glucose metabolism with plasma HDL cholesterol is most likely accounted for by the welldocumented negative association between plasma triglycerides and HDL cholesterol levels as a consequence of cholesteryl ester transfer protein (CETP)-mediated exchange of cholesteryl esters and triglycerides between VLDL and HDL particles (29).…”