title: PGC-1α Promotes Ureagenesis in Mouse Periportal Hepatocytes through SIRT3 and SIRT5 in Response to Glucagon.
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, (15)N-labeled urea and (13)C-labeled glucose production in wild-type mice were significantly increased compared with PGC-1α null mice by [(15)N,(13)C]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.
authors.affiliation: Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Zhengxi
authors.initials: Z
authors.lastname: Bao
authors.affiliation: Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Tongxin
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Feiruo
authors.initials: F
authors.lastname: Huang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005215:Fasting; D015870:Gene Expression / Q000187:drug effects; D005934:Glucagon / Q000097:blood / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D011169:Portal Vein; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014508:Urea / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C542554:SIRT5 protein, mouse; C525046:Sirt3 protein, mouse; D014508:Urea; D005934:Glucagon; D009954:Ornithine Carbamoyltransferase; D056566:Sirtuin 3; D037761:Sirtuins; D002222:Carbamoyl-Phosphate Synthase (Ammonia)