Endogenous fructose production in patients and mice with aldolase B deficiency

Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by aldolase B deficiency (ALDOB). Patients with HFI require lifelong adherence to a fructose-restricted diet. However, despite strict dietary restriction, both HFI patients and mice with Aldob^-/- exhibit hepatocellular accumulation of fructose 1-phosphate (F1P) and intrahepatic lipids (IHL). We studied whether endogenously produced fructose could account for these observations.

We first measured serum fructose levels during a 75 g oral glucose tolerance test (OGTT) in patients with HFI (n = 14) and matched healthy controls (n = 14). Furthermore, we quantified the incorporation of ¹³C₆-glucose into F1P in Aldob^-/- mice (n = 4) and wildtype mice (n = 4). Next, we examined the effects of inhibition of endogenous fructose production in Aldob^-/- mice. Aldob^-/- mice were treated for 9 days with an aldose reductase inhibitor (ARi; n = 9) or vehicle (n = 9) under fructose-free dietary conditions.

Serum fructose concentrations increased significantly at 30 and 60 min compared to baseline in patients with HFI and controls (P < 0.05), indicating glucose-derived fructose production. Similar, ¹³C₆-glucose was incorporated into F1P in Aldob^-/- mice and wildtype mice. ARi-treatment significantly reduced hepatic fructose levels in Aldob^-/- mice (P = 0.002), confirming effective inhibition of the polyol pathway, but did not reduce IHL content (P = 0.71).

Although endogenous fructose production contributes to circulating and hepatic fructose levels in Aldob^-/-, inhibition of the polyol pathway does not reduce hepatic steatosis in Aldob^-/- mice under fructose-free conditions.