Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging

Excessive fat accumulation in liver (hepatic steatosis) predisposes to hepatic functional and structural impairment and overall metabolic risk. Previous studies noted an association between hepatic steatosis and age in humans and rodents. However, the mechanisms leading to age-associated hepatic fat accumulation remain unknown. Earlier work from our group showed that beta-adrenergic receptor (beta-AR) levels and beta-AR-stimulated adenylyl cyclase activity increase in rat liver during aging. Herewe investigated whether age-associated increases in beta-AR signaling play a role in augmenting hepatic lipid accumulation. We demonstrate an increase in hepatic lipid content during senescence and a significant correlation between hepatic fat content and stimulation of adenylyl cyclase activity by the beta-AR agonist isoproterenol in rat liver. Isoproterenol administration to young and old rodents in vivo increased hepatic lipid accumulation. Furthermore, in vitro overexpression of b1-and b2-AR subtypes in hepatocytes from young rodents increased cellular lipid content, whereas inhibition of beta-ARs by receptor subtype-specific inhibitors reduced lipid levels in hepatocytes from senescent animals. Isoproterenol-induced hepatic lipid accumulation in vivo was prevented by the beta-AR nonselective blocker propranolol, suggesting a novel therapeutic effect of this class of drugs in hepatic steatosis. Acipimox, which inhibits adipose tissue lipolysis, did not alter isoproterenolmediated hepatic fat accumulation; thus beta-AR responsive hepatic lipid accumulation does not appear to be related primarily to altered lipolysis. These findings suggest that augmented hepatic beta-AR signaling during aging may increase lipid accumulation in liver and advocate a possible role for beta-adrenergic blockers in preventing or retarding the development of hepatic steatosis. Journal of Endocrinology (2012) 213, 251-261