Figure 1
From: An intronic variant in the GCKR gene is associated with multiple lipids
Increased levels of metabolites in the lipid pathways in carriers of GCKR rs780094-T are marked by red frames, decreased metabolite levels by blue frames, and other metabolites by brown frames. Increased glycolysis stimulates the formation of glycerol-3-phosphate (G3P) and acetyl coenzyme A (acetyl-CoA). G3P conjugates with fatty acyl coenzyme A (FA-CoA) to generate LPA (lysophosphatidic acid) and phosphatidic acid (PA), which is the precursor for all glycerolipids (GLs) and glycerophospholipids (GPLs). GLs are composed of mono- (MAG), di- (DAG), and trisubstituted glycerols (TAG) that are hydrolyzed to free fatty acids (FFAs). GPLs produce phosphatidic acid (PA) and DAG. PA can also be formed via phosphorylation of DAG, and dephosphorylated to generate 1,2-DAG or bound with choline, ethanolamine or inositol to synthetize phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Increased glycolysis and low serine level enhance de novo lipogenesis and the FFA/GL cycling. Acetyl-CoA initiates the de novo lipogenesis pathway by generating saturated fatty acids, such as palmitic acid and monounsaturated fatty acid, oleic acid. The excess of palmitic acid is directed to the FFA/GL cycling by unsaturated fatty acids, such as oleate, and leads to increasing levels of DAG, TAG and GPLs, resulting in fat accumulation in the liver. Low availability of serine leads to an increase in palmitic acid levels, and a decrease in ceramide and lactosylceramide levels. LPC, Lysophosphatidylcholine; LPE, Lysophosphatidylethanolamine.
