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Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease - PubMed

Review

Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease

Amée M Buziau et al. Cell Mol Life Sci. 2020 May.

Abstract

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Keywords: De novo lipogenesis; Fructose; Glucokinase regulatory protein; Hereditary fructose intolerance; Ketohexokinase; Non-alcoholic fatty liver disease.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1

Metabolic consequences of aldolase B deficiency in the liver after an oral fructose load. In physiological states, fructose is rapidly phosphorylated by KHK and subsequently converted by aldolase B to trioses (DHAP and GAH) that enter the glycolytic/gluconeogenic pathways. Aldolase B also catalyzes the conversion of Fru 1,6-P2 to triose phosphates (DHAP and G3P). In aldolase B deficiency, the catabolism of Fru 1P is impaired, and the metabolism of Fru 1,6-P2 is blocked (red bar). Accumulation of Fru 1P has several acute downstream effects denoted in yellow circled letters as follows: (1) depletion of intracellular inorganic phosphate (Pi) and ATP, and consequently formation of IMP and urate (A); (2) impairment of glycogenolysis (by inhibition of GP and loss of Pi) (B) and gluconeogenesis (by inhibition of G6PI) (C), resulting in hypoglycemia; and (3) stimulation of PK activity that—in combination with an impaired gluconeogenesis—promotes hyperlactatemia (D). Further, fructose, which can be produced endogenously from sorbitol (via the polyol pathway), may contribute to the accumulation of Fru 1P (E). Blue cross indicates blocked pathway as a consequence of Fru 1P accumulation. Dashed arrow indicates multiple intermediate enzymatic steps that have not been visualized for simplicity purposes. ADP adenosine diphosphate, AMP adenosine monophosphate, ATP adenosine triphosphate, DHAP dihydroxyacetone phosphate, Fru 6P fructose 6-phosphate, Fru 1P fructose 1-phosphate, Fru 1,6-P2 fructose 1,6-biphosphate, G3P glyceraldehyde 3-phosphate, Glc 6P glucose 6-phosphate, G6PI glucose-6-phosphate isomerase, GAH glyceraldehyde, GP glycogen phosphorylase, IMP inosine monophosphate, KHK ketohexokinase, PEP phosphoenolpyruvate, Pi inorganic phosphate, PK pyruvate kinase

Fig. 2
Fig. 2

Hypothesized pathogenesis of hepatic fat accumulation in aldolase B deficiency. Accumulation of Fru 1P has several chronic downstream effects leading to fat accumulation denoted in yellow circled letters. ALDOB-KO mice fed a low-fructose diet (~ 0.3%) display increased hepatic Fru 1P concentrations. This also seems to be the case in adult HFI patients treated with a fructose-restricted diet, as can be deduced from an abundancy of circulating hypoglycosylated transferrin. Hepatic Fru 1P inhibits glycosylation of transferrin by impairment of MPI (A). Catalytic amounts of Fru 1P dissociate GCK from GKRP in the nucleus, which allows migration of GCK toward the cytosolic space where it converts glucose to Glc 6P and, as a consequence, facilitates hepatic glucose uptake (B). The metabolic fates of an increased hepatic glucose uptake can be: (1) storage as glycogen (C) and (2) storage as fat via DNL with carbons and electrons derived from possibly the pentose phosphate pathway (PPP) (D). Malonyl-CoA, an intermediate of DNL, inhibits fatty acid beta-oxidation (and formation of β-OHB) through impairment of the mitochondrial fatty acid transporter CPTI (E). Of note, alternative mechanisms may contribute to the development of hepatic fat accumulation in aldolase B deficiency as well, such as Fru 1P-induced formation of urate and activation of ChREBP, which both stimulate DNL (see text). Green arrows indicate observations in ALDOB-KO mice. Blue arrows and blue cross indicate observations in HFI patients. Dashed arrow indicates multiple intermediate enzymatic steps that have not been visualized for simplicity purposes. ACC acetyl-CoA carboxylase, ACL ATP-citrate lyase, ALDOB aldolase B, β-OHB beta-hydroxybutyrate, CPTI carnitine palmitoyltransferase I, DHAP dihydroxyacetone phosphate, ER endoplasmic reticulum, Fru 6P fructose 6-phosphate, FAS fatty acid synthase, Fru 1P fructose 1-phosphate, Fru 1,6-P2 fructose 1,6-biphosphate, G3P glyceraldehyde 3-phosphate, Glc 6P glucose 6-phosphate, GAH glyceraldehyde, GCK glucokinase, GKRP glucokinase regulatory protein, M6P mannose 6-phosphate, MPI mannose-6-phosphate isomerase, NADPH nicotinamide adenine dinucleotide phosphate, PPP pentose phosphate pathway

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