Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand binding studies demonstrated that β-AR density increased by >3-fold in hepatocyte membranes from senescent (24 mo old) compared to young adult (7 mo old) rats, and that this phenomenon was blocked by food restriction which is known to retard aging processes in rodents. Competition binding studies revealed a mixed population of β1- and β2-AR subtypes in liver membranes over the adult life span, with a trend for greater β2-AR density with age. Expression of both β-AR subtype mRNAs in rat liver increased with age, while β2- but not β1-AR protein levels declined in livers of old animals. Immunoreactive β2- but not β1-ARs were preferentially distributed in pericentral hepatic regions. Levels of GRK2/3 and β-arrestin 2 proteins, which are involved in downregulation of agonist-activated GPCRs including β-ARs, increased during aging. Insofar as sympathetic tone increases with age, our findings suggest that, despite enhanced agonist-mediated downregulation of hepatic β-ARs preferentially affecting the β2-AR subtype, increased generation of both receptor subtypes during aging augments the pool of plasma membrane bound β-ARs coupled to AC in hepatocytes. This study thus identifies one or both β-AR subtypes as possible therapeutic targets involved in aberrant hepatic processes of glucose and lipid metabolism during aging.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AECQaB
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