β-Adrenergic Agonist and Antagonist Regulation of Autophagy in HepG2 Cells, Primary Mouse Hepatocytes, and Mouse Liver

Abstract

Autophagy recently has been shown to be involved in normal hepatic function and in pathological conditions such as non-alcoholic fatty liver disease. Adrenergic signalling also is an important regulator of hepatic metabolism and function. However, currently little is known about the potential role of adrenergic signaling on hepatic autophagy, and whether the β-adrenergic receptor itself may be a key regulator of autophagy. To address these issues, we investigated the actions of the β2-adrenergic receptor agonist, clenbuterol on hepatic autophagy. Surprisingly, we found that clenbuterol stimulated autophagy and autophagic flux in hepatoma cells, primary hepatocytes and in vivo. Similar effects also were observed with epinephrine treatment. Interestingly, propranolol caused a late block in autophagy in the absence and presence of clenbuterol, both in cell culture and in vivo. Thus, our results demonstrate that the β2- adrenergic receptor is a key regulator of hepatic autophagy, and that the β-blocker propranolol can independently induce a late block in autophagy.

β-Adrenergic induction of lipolysis in hepatocytes is inhibited by ethanol exposure

“…Several lines of evidence link cAMP elevation to induction of autophagy in hepatocytes. First, Farah et al (45) demonstrated that ␤-AR agonists induce LC3-II formation and p62 degradation in primary mouse hepatocytes and human hepatoma cells. Another study showed that caffeine, an adenosine receptor antagonist and phosphodiesterase inhibitor, stimulates lipid metabolism and autophagy (LC3-II increase and p62 decrease), as well as suppresses mTORC1 activity (46).…”

Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

“…For T 3 treatments, all cells were grown for at least 3 days in DMEM containing 10% Dowex-stripped FBS and 1ϫ penicillin/streptomycin (normal T 3 -depleted DMEM) before adding T 3 (100 nM; unless mentioned otherwise) with or without other compounds (LY292004, 5 M) at indicated durations in the respective figures. Primary mouse hepatocytes were isolated from male C57BL/6 mice (8 -10 weeks old) using standard twostep collagenase perfusion method, as mentioned previously (26), and cultured in normal T 3 -depleted DMEM as mentioned above.…”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…Loss of lipin‐1 expression has been shown to reduce DAG levels and impair autophagic flux by preventing the normal maturation of autolysosomes during the process of autophagy . Recent studies have confirmed that propranolol blocks the late stages of autophagy, mimicking responses in cells lacking lipin‐1 expression . Lipin‐1 also operates as a transcriptional coactivator, where it is involved in the regulation of lipid metabolism.…”

“…231 Recent studies have confirmed that propranolol blocks the late stages of autophagy, mimicking responses in cells lacking lipin-1 expression. 232,233 Lipin-1 also operates as a transcriptional coactivator, where it is involved in the regulation of lipid metabolism.…”