Uric acid and transforming growth factor in fructose-induced production of reactive oxygen species in skeletal muscle

Abstract

The consumption of fructose, a major constituent of the modern diet, has raised increasing concern about the effects of fructose on health. Research suggests that excessive intake of fructose (>50 g/d) causes hyperuricemia, insulin resistance, mitochondrial dysfunction, de novo lipogenesis by the liver, and increased production of reactive oxygen species (ROS) in muscle. In a number of tissues, uric acid has been shown to stimulate the production of ROS via activation of transforming growth factor β1 and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4. The role of uric acid in fructose-induced production of ROS in skeletal muscle, however, has not been investigated. This review examines the evidence for fructose-induced production of ROS in skeletal muscle, highlights proposed mechanisms, and identifies gaps in current knowledge.

Keywords: fructose; mitochondrial dysfunction; reactive oxygen species; transforming growth factor; uric acid.

Figure 1

Effects of reactive oxygen species (ROS) accumulation on cellular functions. ROS induce DNA damage, protein oxidation, and lipid peroxidation, which cause mitochondrial dysfunction via impaired mitochondrial respiration and reduced ATP production.

Figure 2

Fructose-induced activation of the purine pathway. Fructose is rapidly phosphorylated in the hepatocyte by ketohexokinase (KHK) to fructose-1-phosphate, which uses adenosine triphosphate (ATP) as a phosphate donor. Intracellular phosphate (PO₄) levels decrease, stimulating the activity of adenosine monophosphate (AMP) deaminase 2 (AMPD2). AMPD2 converts AMP to inosine monophosphate (IMP). IMP is metabolized to inosine by 5′ nucleotidase (5′ NT), which is further degraded to xanthine by purine nucleoside phosphorylase (PNP). Xanthine is converted to hypoxanthine by xanthine oxidase (XO), ultimately generating uric acid. This pathway may be inhibited by the XO inhibitor, allopurinol.

Figure 3

Proposed pathway of fructose-induced ROS production in skeletal muscle. NADPH oxidase-4 (Nox4)-induced oxidative stress in response to fructose-induced production of uric acid, which upregulates transforming growth factor (TGF)-β1. TGF-β1 induces Nox4 activation and Nox4-dependent mitochondrial ROS generation. Inhibition of uric acid production by allopurinol, together with inhibition of TGF-β1 signaling TGF-β1-specific receptor inhibitor and Nox4 with small interfering RNA (siRNA), abrogates induction of Nox4 and subsequent ROS production.