Acetylcholine affects rat liver metabolism via type 3 muscarinic receptors in hepatocytes.
Although the role of acetylcholine (Ach) in hepatic glucose metabolism is well elucidated, it is still unclear if it influences gluconeogenesis, glycogenolysis and high-energy phosphate metabolism, and if it does what the mechanisms of this influence are. Therefore, using isolated perfused rat liver as a model, we have studied the effect of Ach on oxygen consumption, synthesis of glucose from lactate and pyruvate, glycogen formation, mitochondrial oxidative phosphorylation and ATP-synthesis. We have established that effects of Ach on oxygen consumption depend on its concentration. When used at a concentration of 10(-7) M, Ach exerts maximum stimulatory effect, while its infusion at 10(-6) M causes a decrease of oxygen consumption by the liver. Moreover, when used at a concentration of 10(-6) M or 10(-7) M, Ach increases rates of glucose production from the gluconeogenic substrates lactate and pyruvate, leading to enhanced glycogen content in perfused liver. It was also shown that Ach possesses a stimulating effect on alanine and aspartate aminotransferases. As detected by 31P NMR spectroscopy, continuous liver perfusion with pyruvate and lactate in the presence of Ach leads to a significant decrease of ATP level, implying enhanced energy requirements for gluconeogenesis under these conditions. Elimination of the described effects of Ach by atropine, the antagonist of muscarinic receptors, and identification of the type 3 muscarinic receptors (m3) in isolated hepatocytes as well as in whole liver, imply that Ach may exert its effect on liver metabolism through m3 receptors.
Vatamaniuk
M Z
MZ
Biochemistry & Biophysics Department, University of Pennsylvania, 501 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104, USA. marcovk@mail.med.upenn.edu
Horyn
O V
OV
Vatamaniuk
O K
OK
Doliba
N M
NM
D000109:Acetylcholine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000096:biosynthesis; D006003:Glycogen / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010477:Perfusion; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D011976:Receptors, Muscarinic; D001285:Atropine; D000255:Adenosine Triphosphate; D006003:Glycogen; D005947:Glucose; D000109:Acetylcholine