Dietary calorie restriction in mice induces carbamyl phosphate synthetase I gene transcription tissue specifically.
Dietary calorie restriction (CR) delays age-related physiologic changes, increases maximum life span, and reduces cancer incidence. Here, we present the novel finding that chronic reduction of dietary calories by 50% without changing the intake of dietary protein induced the activity of mouse hepatic carbamyl phosphate synthetase I (CpsI) 5-fold. In liver, CpsI protein, mRNA, and gene transcription were each stimulated by approximately 3-fold. Thus, CR increased both the rate of gene transcription and the specific activity of the enzyme. Short-term feeding studies demonstrated that higher cpsI expression was due to CR and not consumption of more dietary protein. Intestinal CpsI activity was stimulated 2-fold, while its mRNA level did not change, suggesting enzyme activity or translation efficiency was stimulated. CpsI catalyzes the conversion of metabolic ammonia to carbamyl phosphate, the rate-limiting step in urea biosynthesis. cpsI induction suggests there is a shift in the metabolism of calorie-restricted animals toward protein catabolism. CpsI induction likely facilitates metabolic detoxification of ammonia, a strong neurotoxin. Enhanced protein turnover and metabolic detoxification may extend life span. Physiologic similarities between calorie-restricted and hibernating animals suggest the effects of CR may be part of a spectrum of adaptive responses that include hibernation.
Tillman
J B
JB
Department of Biochemistry, University of California, Riverside, California 92521, USA.
Dhahbi
J M
JM
Mote
P L
PL
Walford
R L
RL
Spindler
S R
SR
D000818:Animals; D001835:Body Weight; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000096:biosynthesis* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004038:Diet, Reducing; D004044:Dietary Proteins; D002149:Energy Intake; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008815:Mice, Inbred Strains; D018075:RNA, Complementary; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D014158:Transcription, Genetic / Q000187:drug effects
D004044:Dietary Proteins; D018075:RNA, Complementary; D012333:RNA, Messenger; D003609:Dactinomycin; D002222:Carbamoyl-Phosphate Synthase (Ammonia)