Altered Expression of Hepatic {beta}-Adrenergic Receptors in Aging Rats: Implications for Age-Related Metabolic Dysfunction in Liver

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.

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