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

Abstract

In liver steatosis ( fatty liver), hepatocytes accumulate many large neutral lipid storage organelles known as lipid droplets (LDs). LDs are important in the maintenance of energy homeostasis, but the signaling mechanisms that stimulate LD metabolism in hepatocytes are poorly defined. In adipocytes, catecholamines target the β-adrenergic (β-AR)/cAMP pathway to activate cytosolic lipases and induce their recruitment to the LD surface. Therefore, the goal of this study was to determine whether hepatocytes, like adipocytes, also undergo cAMP-mediated lipolysis in response to β-AR stimulation. Using primary rat hepatocytes and human hepatoma cells, we found that treatment with the β-AR agent isoproterenol caused substantial LD loss via activation of cytosolic lipases adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). β-Adrenergic stimulation rapidly activated PKA, which led to the phosphorylation of ATGL and HSL and their recruitment to the LD surface. To test whether this β-AR-dependent lipolysis pathway was altered in a model of alcoholic fatty liver, primary hepatocytes from rats fed a 6-week EtOH-containing Lieber-DeCarli diet were treated with cAMP agonists. Compared with controls, EtOH-exposed hepatocytes showed a drastic inhibition in β-AR/cAMP-induced LD breakdown and the phosphorylation of PKA substrates, including HSL. This observation was supported in VA-13 cells, an EtOH-metabolizing human hepatoma cell line, which displayed marked defects in both PKA activation and isoproterenol-induced ATGL translocation to the LD periphery. In summary, these findings suggest that β-AR stimulation mobilizes cytosolic lipases for LD breakdown in hepatocytes, and perturbation of this pathway could be a major consequence of chronic EtOH insult leading to fatty liver.

Role of cAMP and phosphodiesterase signaling in liver health and disease

“…Moreover, a PKA specific agonist increased CPT1A levels in primary hepatocytes [74]. In addition to fatty acid oxidation, inhibition of lipid droplet lipolysis via cytosolic lipases in alcohol-exposed hepatocytes has been recently demonstrated [75]. This inhibition was mediated by the inability of alcohol-exposed hepatocytes to activate PKA in response to β-adrenergic stimulation and recruitment of lipases to lipid droplets.…”

Impaired Rab7 and dynamin2 block fat turnover by autophagy in alcoholic fatty livers

“…These findings suggest that cytosolic lipases are also important regulators in LD turnover in hepatocytes (2). Interestingly, a more recent study reported that hepatocytes isolated from chronic ethanol-fed rats or acute ethanol-treated hepatoma cells that can metabolize ethanol showed significantly perturbed β-adrenergic stimuli-induced LD breakdown (3). Mechanistically, they found that ethanol inhibited PKA-mediated phosphorylation of HSL and the recruitment of ATGL to the LD surface resulting in the blockage of LD catabolism (3).…”

“…Interestingly, a more recent study reported that hepatocytes isolated from chronic ethanol-fed rats or acute ethanol-treated hepatoma cells that can metabolize ethanol showed significantly perturbed β-adrenergic stimuli-induced LD breakdown (3). Mechanistically, they found that ethanol inhibited PKA-mediated phosphorylation of HSL and the recruitment of ATGL to the LD surface resulting in the blockage of LD catabolism (3). In addition to the above lipase-mediated LD breakdown, another emerging pathway to breakdown LD in hepatocytes involves the lipases and acidic hydrolases in lysosomes, a process known as “lipophagy”(4).…”

Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review.

“…Therapeutic targets to manipulate the lipid metabolism during NMP involve mainly the modulation of the production of enzymes involved with oxidation of FA for energy production and/or FA cellular exportation. As a consequence, cytoplasmic lipases play a key role as initiators in the mobilization of intracellular triacylglycerol stores and conversion into FAs and glycerol . Between those lipases, the adipose triglyceride lipase (ATGL) is considered to be the limiting rate factor for intracellular lipolysis in hepatocytes .…”