Figure 7.

Hepatic metabolism of circulating fructose into lipogenic pathways. Upon fructose uptake largely via the hepatic GLUT2 transporter, it is converted largely to fructose-1-P by ketohexokinase (KHK) and to a lesser extent to fructose-6-P by hexokinase (HK). Fructose-6-P is then phosphorylated to fructose-1,6-BiP by phosphofructose kinase (PFK). Fructose-1,6-BiP is then in turn converted by aldolases A & C to glyceraldehyde-3-P (GA-3-P), which via sequential enzymatic steps catalyzed by GA-3-P dehydrogenase, 3-phosphoglycerate kinase 1/2 complex, glyceromutase, and pyruvate kinase is then converted to pyruvate. Pyruvate is taken up into the mitochondria via the mitochondrial pyruvate carrier and fed into the Kreb's/Tricarboxylic acid (TCA) cycle. Fructose-1-P on the other hand, is converted to dihydroxyacetone (DHAP) and to GA via aldolases B and C. Both GA and DHAP can then be converted to glycerol-3-P (G-3-P), the precursor of triglyceride (TG) synthesis. Citrate derived from pyruvate in the TCA cycle is converted by ATP-citrate lyase/synthase (ACLY) to acetyl CoA, which is in turn converted into malonyl CoA by acetyl CoA carboxylase 1 (ACC1), and thence into fatty acid (FA; palmitic acid) synthesis catalyzed by FA-synthase (FAS). Malonyl CoA inhibits FA import into the mitochondria by blocking carnitine palmitoyl-transferase (CPT1a) thereby blocking FA-β-oxidation (β-Oxid). Palmitic acid (C16:O) can be elongated to stearic acid (C18:O), whereas these FAs can be desaturated to palmitoleic (C16:1) and oleic (C18:1) acids, respectively, via stearoyl CoA desaturase (SCD1). Thus, hepatic uptake of circulating fructose leads to increased hepatic FA- and TG-accumulation, under normal conditions. Although glucose uptake shares some of the same metabolic intermediates, a relevant difference is that ATP, citrate and acidic pH generated via the TCA cycle exert a critical allosteric block at the rate-limiting enzyme PHK, but not of KHK²³⁸. This would limit glucose or fructose-derived fructose-6-P from further contributing to the FA- and TG-accumulation. By contrast, without such a block, fructose could proceed unimpeded via fructose-1-P to keep contributing to hepatic FA- and TG-syntheses and accumulation as TG-macrovesicles that are normally packaged along with apolipoprotein B 100 (ApoB 100) and exported as VLDL/LDL. Glycerol-3-P acetyltransferase (GPAT); acylglycerol-3-P acetyltransferase AGPAT; elongation of very long fatty acids protein 6 (ELOV6); lipid phosphatidate phosphatase LIPIN1; diacylglycerol-O-acyltransferase, DGAT2; very low-density lipoprotein, (VLDL). Scheme adapted from Park et al.²⁴¹ and Softic et al.²⁴².