Mechanisms responsible for regulation of branched-chain amino acid catabolism

https://doi.org/10.1016/j.bbrc.2003.11.007Get rights and content

Abstract

The branched-chain amino acids (BCAAs) are essential amino acids and therefore must be continuously available for protein synthesis. However, BCAAs are toxic at high concentrations as evidenced by maple syrup urine disease (MSUD), which explains why animals have such an efficient oxidative mechanism for their disposal. Nevertheless, it is clear that leucine is special among the BCAAs. Leucine promotes global protein synthesis by signaling an increase in translation, promotes insulin release, and inhibits autophagic protein degradation. However, leucine’s effects are self-limiting because leucine promotes its own disposal by an oxidative pathway, thereby terminating its positive effects on body protein accretion. A strong case can therefore be made that the proper leucine concentration in the various compartments of the body is critically important for maintaining body protein levels beyond simply the need of this essential amino acid for protein synthesis. The goal of the work of this laboratory is to establish the importance of regulation of the branched chain α-ketoacid dehydrogenase complex (BCKDC) to growth and maintenance of body protein. We hypothesize that proper regulation of the activity state of BCKDC by way of its kinase (BDK) and its phosphatase (BDP) is critically important for body growth, tissue repair, and maintenance of body protein. We believe that growth and protection of body protein during illness and stress will be improved by therapeutic control of BCKDC activity. We also believe that it is possible that the negative effects of some drugs (PPARα ligands) and dietary supplements (medium chain fatty acids) on growth and body protein maintenance can be countered by therapeutic control of BCDKC activity.

Section snippets

Leucine has important effects above and beyond its role as an essential amino acid. Leucine signals an increase in protein synthesis

Animals cannot synthesize the BCAAs. The BCAAs are therefore essential amino acids and must be continuously supplied by the diet for growth and good health. A diet lacking just one of the essential amino acids will throw an animal into negative nitrogen balance and cause loss of body weight. Diets deficient in protein relative to energy likewise limit the supply of essential amino acids, restrict protein synthesis, and inhibit growth. Overall, the BCAAs are like other essential amino acids in

There is much evidence scattered throughout the literature suggesting that BCAAs and proper regulation of BCAA catabolism are important for growth and maintenance of body protein

Supplementation of the diet of pigs with carnitine reduces backfat thickness, decreases lipid deposition, and increases protein accretion [46]. Of great interest to the meat industry, this could also be an important finding for human nutrition. Carnitine is proposed, as would be expected, to bring about these effects by promoting fatty acid oxidation [46]. This in turn is pictured to induce greater anaplerosis by pyruvate carboxylase and reduced flux through BCKDC [46]. The consequence is

Medium-chain triglycerides and PPARα ligands promote the catabolism of BCAAs

In a nutshell, we believe that under certain conditions medium chain triglycerides and PPARα ligands can cause inhibition of BDK activity, which in turn increases BCKDC activity, and therefore lowers blood and tissue BCAA levels. The latter can decrease protein synthesis, either because BCAA levels are too low or the stimulatory effect of leucine on protein translation is lost. This may only be a problem when dietary protein levels are marginally adequate or restricted. The problem may go

Can BCAA be used to promote growth, improve muscle protein accretion, and help maintain body protein in various diseases and during ageing?

We believe that BCAAs have potential as therapeutic agents for the treatment of a number of medical conditions (liver failure, anorexia, cachexia, chronic inflammatory disease, and muscle wasting of ageing). Leucine is special among the BCAAs because of its ability to promote protein translation, decrease protein degradation, and promote insulin release. Valine and isoleucine do not have these effects but are nevertheless important since the proper ratios of the BCAAs must be maintained for the

Acknowledgements

This work was supported by grants from US Public Health Service (NIH DK 19259; R.A.H.), the Grace M. Showalter Residuary Trust (R.A.H.), and the Midwest American Heart Association (N.H.J.).

References (70)

  • K.M. Popov et al.

    Dietary control and tissue specific expression of branched-chain alpha-ketoacid dehydrogenase kinase

    Arch. Biochem. Biophys

    (1995)
  • R. Kobayashi et al.

    Experimental hyperthyroidism causes inactivation of the branched-chain alpha-ketoacid dehydrogenase complex in rat liver

    Arch. Biochem. Biophys

    (2000)
  • R.A. Harris et al.

    Physiological covalent regulation of rat liver branched-chain alpha-ketoacid dehydrogenase

    Arch. Biochem. Biophys

    (1985)
  • P.A. Lazo

    Tumour induction of host leucine starvation

    FEBS Lett

    (1981)
  • W.E. Mitch et al.

    Memorial award in clinical nutrition lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease

    Am. J. Clin. Nutr

    (1998)
  • S.M. Hutson et al.

    Function of leucine in excitatory neurotransmitter metabolism in the central nervous system

    J. Nutr

    (2001)
  • D.W. Gietzen et al.

    Molecular mechanisms in the brain involved in the anorexia of branched-chain amino acid deficiency

    J. Nutr

    (2001)
  • J.C. Anthony et al.

    Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine

    J. Nutr

    (2001)
  • D.K. Layman

    The role of leucine in weight loss diets and glucose homeostasis

    J. Nutr

    (2003)
  • J.C. Anthony et al.

    Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway

    J. Nutr

    (2000)
  • S. Mordier et al.

    Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway

    J. Biol. Chem

    (2000)
  • G.E. Mortimore et al.

    Leucine-specific binding of photoreactive Leu7-MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte

    Biochem. Biophys. Res. Commun

    (1994)
  • D. Dardevet et al.

    Stimulation of in vitro rat muscle protein synthesis by leucine decreases with age

    J. Nutr

    (2000)
  • I. Rieu et al.

    Leucine-supplemented meal feeding for ten days beneficially affects postprandial muscle protein synthesis in old rats

    J. Nutr

    (2003)
  • M.C. Powanda et al.

    Metabolic effects of infection on protein and energy status

    J. Nutr

    (2003)
  • M.H. Golden

    The development of concepts of malnutrition

    J. Nutr

    (2002)
  • F. Du et al.

    Food intake, energy balance and serum leptin concentrations in rats fed low-protein diets

    J. Nutr

    (2000)
  • N.J. Rothwell et al.

    Mechanisms of thermogenesis induced by low protein diets

    Metabolism

    (1983)
  • K. Hayase et al.

    Triiodothyronine administration affects urea synthesis in rats

    J. Nutr

    (1991)
  • U. Keller et al.

    Effects of medium- and long-chain fatty acids on whole body leucine and glucose kinetics in man

    Metabolism

    (2002)
  • J.M. Liet et al.

    Leucine metabolism in preterm infants receiving parenteral nutrition with medium-chain compared with long-chain triacylglycerol emulsions

    Am. J. Clin. Nutr

    (1999)
  • R. Paxton et al.

    Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain alpha-ketoacid dehydrogenase kinase in vitro and in perfused rat heart

    Arch. Biochem. Biophys

    (1984)
  • A.E. Harper et al.

    Branched-chain amino acid metabolism

    Annu. Rev. Nutr

    (1984)
  • S.J. Yeaman

    The 2-oxo acid dehydrogenase complexes: recent advances

    Biochem. J

    (1989)
  • Z. Damuni et al.

    Purification and properties of branched-chain alpha-keto acid dehydrogenase phosphatase from bovine kidney

    Proc. Natl. Acad. Sci. USA

    (1984)
  • Cited by (140)

    • SGLT2 inhibitor-empagliflozin treatment ameliorates diabetic retinopathy manifestations and exerts protective effects associated with augmenting branched chain amino acids catabolism and transportation in db/db mice

      2022, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      In addition to substrate-dependent allosteric modulation, BCKD activity is also regulated by post-translational modifications. Phosphorylation of the BCKD E1α subunit by BCKD kinase (BCKDK) inhibits BCKD [26], whereas dephosphorylation by protein phosphatase 2Cm (PP2Cm) activates BCKD [27]. Subsequently, the expression of BCKDK, BCKDHA, and BCKDHB was measured.

    • Cardiac Metabolism, Reprogramming, and Diseases

      2024, Journal of Cardiovascular Translational Research
    View all citing articles on Scopus
    View full text