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 ?M) 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.
1.Sabourin, P.J., and Bieber, L.L.Formation of β-hydroxyisovalerate by an α-ketoisocaproate oxygenase in human liverMetabolism32(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-methylbutyrateCancer 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 lossCancer 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 mellitusClin. Chim. Acta188(2)161-168(1990)