Abstract
Excess ammonia is produced during fasting when amino acids are used for glucogenesis. Together with ureagenesis, glucogenesis occurs in periportal hepatocytes mediated mainly through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In vivo experiments showed that fasting strongly stimulated mice glucagon secretion, hepatic PGC-1α, sirtuin 3 (SIRT3) and sirtuin 5 (SIRT5) expression and ureagenesis enzymatic activity such as carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamoylase (OTC). Interestingly, 15N-labeled urea and 13C-labeled glucose production in wild-type mice were significantly increased compared with PGC-1α null mice by [15N,13C]alanine perfused liver. Glucagon significantly stimulated ureagenesis, expression of SIRT3, SIRT5 and the activities of CPS1 and OCT but did not stimulate PGC-1α silencing hepatocytes in mice periportal hepatocytes. Contrarily, PGC-1α overexpression significantly increased the expression of SIRT3, SIRT5 and the activities of CPS1 and OTC, but induced no significant changes in CPS1 and OTC expression. Morever, SIRT3 directly deacetylates and upregulates the activity of OTC, while SIRT5 deacetylates and stimulates the activity of CPS1. During fasting, PGC-1α facilitates ureagenesis in mouse periportal hepatocytes by deacetylating CPS1 and OTC modulated by mitochondrial deacetylase, SIRT3 and SIRT5. This mechanism may be relevant to ammonia detoxification and metabolic homeostasis in liver during fasting.
Highlights
Excess ammonia is produced during fasting when amino acids are used for glucogenesis
In terms of its contribution to the problem of diet-dependent maintenance of energy homeostasis, there is a body of evidence to suggest that PGC-1α is important for the compensatory metabolic responses that occur during food deprivation[13]
New evidences suggest that sirtuin 3 (SIRT3) and sirtuin 5 (SIRT5) do interact with PGC-1α in liver[15,19]
Summary
Excess ammonia is produced during fasting when amino acids are used for glucogenesis. PGC-1α facilitates ureagenesis in mouse periportal hepatocytes by deacetylating CPS1 and OTC modulated by mitochondrial deacetylase, SIRT3 and SIRT5. This mechanism may be relevant to ammonia detoxification and metabolic homeostasis in liver during fasting. A time when AA becomes an important energy source, the flow of carbon from AA into central metabolism is promoted by hepatic gluconeogenesis[3,4,5] Under these conditions there is excess ammonia production, which is converted to urea for ammonia detoxification[6,7]. Hormonal and nutritional regulation of hepatic gluconeogenesis occurs mainly through modulation of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α )[12]. The regulatory mechanism of ureagenesis during fasting and administration of glucagon was demonstrated
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