title: Role of β-adrenergic receptors in regulation of hepatic fat accumulation during aging.
abstract: 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 β-adrenergic receptor (β-AR) levels and β-AR-stimulated adenylyl cyclase activity increase in rat liver during aging. Here we investigated whether age-associated increases in β-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 β-AR agonist isoproterenol in rat liver. Isoproterenol administration to young and old rodents in vivo increased hepatic lipid accumulation. Furthermore, in vitro overexpression of β1- and β2-AR subtypes in hepatocytes from young rodents increased cellular lipid content, whereas inhibition of β-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 β-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 isoproterenol-mediated hepatic fat accumulation; thus β-AR responsive hepatic lipid accumulation does not appear to be related primarily to altered lipolysis. These findings suggest that augmented hepatic β-AR signaling during aging may increase lipid accumulation in liver and advocate a possible role for β-adrenergic blockers in preventing or retarding the development of hepatic steatosis.
authors.affiliation: Geriatric Research, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA.
authors.forename: Paramita M
authors.initials: PM
authors.lastname: Ghosh
authors.forename: Zhen-Ju
authors.initials: ZJ
authors.lastname: Shu
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Zhongding
authors.initials: Z
authors.lastname: Lu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.forename: Chih-Ko
authors.initials: CK
authors.lastname: Yeh
authors.forename: Bin-Xian
authors.initials: BX
authors.lastname: Zhang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Katz
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamat
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005223:Fats / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D005223:Fats; D007093:Imidazoles; D008055:Lipids; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; D011433:Propranolol; C049763:CGP 20712A; D000262:Adenylyl Cyclases; D007545:Isoproterenol