Role of branched chain amino acids in cerebral ammonia homeostasis related to hepatic encephalopathy.
Hepatic encephalopathy (HE) is associated with increased ammonia levels in plasma and brain. Different treatment strategies have been developed to ameliorate the detrimental effects of the ammonia load. One such strategy is based on the finding of a low level of the branched chain amino acids (BCAAs) in plasma of patients suffering from HE and the assumption that in particular isoleucine could be beneficial to brain energy metabolism as it is metabolized to the tricarboxylic acid cycle intermediate and precursor succinyl-CoA and acetyl-CoA, respectively. This would enable de novo synthesis of glutamine via α-ketoglutarate and glutamate and at the same time stimulate oxidative metabolism. The present mini-review summarizes the metabolic basis for this hypothesis delineating studies in the brain in vivo as well as in cultured neural cells aimed at elucidating the metabolism of the BCAAs focusing on isoleucine. The conclusion is that isoleucine appears at least partially to act in this fashion albeit its metabolism is quantitatively relatively modest. In addition, a short section on the role of the BCAAs in synaptic ammonia homeostasis is included along with some thoughts on the role of the BCAAs in other pathologies such as cancer.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark. laba@sund.ku.dk
Lasse K
LK
Bak
Helle S
HS
Waagepetersen
Michael
M
Sørensen
Peter
P
Ott
Hendrik
H
Vilstrup
Susanne
S
Keiding
Arne
A
Schousboe
D000597:Amino Acids, Branched-Chain / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D002952:Citric Acid Cycle / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D022124:Hyperammonemia / Q000188:drug therapy / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism
D000597:Amino Acids, Branched-Chain; D000641:Ammonia