. Author manuscript; available in PMC: 2015 Dec 1.

Published in final edited form as: Nat Rev Endocrinol. 2014 Oct 7;10(12):723–736. doi: 10.1038/nrendo.2014.171

Table 1.

Short and long-term regulation of BCKDC activity

Regulator	Duration of effect	Effect on BCKDK (activity or expression)	Effect on total BCKDC activity (or subunit expression)	Expected or known effect on BCKDC actual activity or activity state	Organ, tissue, cell affected or in vitro findings
Clofibrate	Short term and long term	Inhibition of enzyme activity (directly) and ↓protein levels	↑ Expression of subunits and ↑ total activity	↑ Percentage of active enzyme	Liver; other PPAR-α agonists have long-term effects but no allosteric effects¹⁸⁹
Exercise	Short term	Inhibition of binding to complex	No change	Activation	Skeletal muscle¹⁹⁰ and liver¹⁹¹ (↓ binding of BCKDK to BCKDC)
Glucocorticoids	Long term	↓ Protein levels and ↓ gene expression¹⁹²	No change	Activation	Kidney cell line (BCKDK studies); other studies on liver hypothesized effects of methylpredisone due to ↑ plasma levels of leucine¹⁹³
High-protein diet	Long term	↓ Protein levels	↑	↑	Liver^194–196
Insulin	Long term	↑ Protein levels	No change	↓ or no change	No change in healthy animals following insulin administration or in 3T3-L1 cells stimulated with insulin;⁶³ ↓BCKDH activity in liver of methylpredisone-treated rats correlates with plasma levels of leucine;¹⁹³ clone 9 cells: effects attenuated by mTORC1 and PI3-K inhibition¹⁹⁷
Low-protein diet or protein starvation	Long term	↑ Protein levels	↓	↓	Liver^{194,196,198,199}
Medium-chain fatty acids (MCFAs)	Short term	Inhibition observed with octanoate on purified kinase	NA	↑ is expected, but in cells MCFAs also elicit ↓BCKDC activity via ↑NADH:NAD⁺ ratio and acetyl-CoA¹⁴³	Purified kinase;²⁰⁰ uncertainty between the balance of kinase vs FFA inhibition
Oleate or palmitoylcarnitine	Short term	NA	NA	↓	Liver cells and muscle cells^98,175–177
Sepsis, IL-1 and TNF	Long term	NA	NA	↑	Skeletal muscle: effect prevented by cortisone treatment²⁰¹
Starvation^*	Short term and long term	Short term: ↑ BCAA R_a and BCKAs inhibit BCKDK Long term: ↑BCKDK activity in liver	No change	Activation	Liver^202,203
STZ-induced diabetes mellitus	Long term	Skeletal muscle: ↓ BCKDK protein levels without affecting gene expression Cardiac muscle: ↑ protein levels ↑ and gene expression Liver: ↓ mass of BCKDK; no change in gene expression	Skeletal muscle: ↑ activity, ↑protein levels of E1-α, E1-β and E2 subunit, and ↑ gene expression Cardiac muscle: ↓ activity, no effect on protein levels or gene expression of subunits Liver: ↑ total BCKAD activity with diabetes, ↑ mass of each BCKDH subunit, no change in gene expression	Skeletal muscle: ↑ activity state and ↓ rate of inactivation Cardiac muscle: ↓ activity state and ↑ rate of inactivation Liver: diabetes increases the activity state	Liver, heart and muscle^{202,204–207}
T₃	Long term	↑	Not affected	↓	Liver²⁰⁸
α-KIC	Short term	Inhibition	Not affected	↑	All tissues tested showed inhibition of the kinase by α-KIC^198,209
PPAR-γ agonists	Long term	No effect	↑ Protein levels and ↑ gene expression	↑ Predicted	Adipose tissue^63,210

Starvation for all food and just protein or low-protein diets have opposite effects. Abbreviations: BCKDC, branched-chain α-ketoacid dehydrogenase complex; BCKDK, branched-chain α-ketoacid dehydrogenase kinase; α-KIC, α-ketoisocaproate; mTORC1, mammalian target of rapamycin complex 1; FFA, free fatty acid; NA, not available; PPAR, peroxisome proliferator-activated receptor; PI3-K, phosphoinositide 3-kinase; STZ, streptozotocin; TNF, tumour necrosis factor.