β-Hydroxyisovaleric Acid

β-Hydroxyisovaleric acid is an active metabolite of L-leucine.¹ It is produced from leucine via an α-ketoisocaproic acid intermediate by α-ketoisocaproate oxidase in human liver homogenates. β-Hydroxyisovaleric acid (50 µM) reduces increases in 20S proteasome activity and NF-κB nuclear accumulation induced by proteolysis-inducing factor (PIF) in C2C12 myotubes.² It inhibits protein degradation and stimulates protein synthesis in the gastrocnemius muscle of cachectic mice bearing MAC16 tumors when administered at doses of 0.25 and 2.5 g/kg.³ Urinary levels of β-hydroxyisovaleric acid are increased in patients with type II diabetes.⁴ Formulations containing β-hydroxyisovaleric acid have been used as dietary supplements.

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1. Sabourin, P.J., and Bieber, L.L. Formation of β-hydroxyisovalerate by an α-ketoisocaproate oxygenase in human liver. Metabolism 32(2), 160-164 (1983).

2. Smith, H.J., Wyke, S.M., and Tisdale, M.J. Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate. Cancer Res. 64(23), 8731-8735 (2004).

3. Smith, H.J., Mukerji, P., and M.J., T. Attenuation of proteasome-induced proteolysis in skeletal muscle by β-hydroxy-β-methylbutyrate in cancer-induced muscle loss. Cancer Res. 65(1), 277-283 (2005).

4. Yu, W.M., Kuhara, T., Inoue, Y., et al. Increased urinary excretion of β-hydroxyisovaleric acid in ketotic and non-ketotic type II diabetes mellitus. Clin. Chim. Acta 188(2), 161-168 (1990).