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

ABSTRACT: In liver steatosis (i.e. 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 ?-adrenergic (?-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 ?-AR stimulation. Using primary rat hepatocytes and human hepatoma cells, we found that treatment with the ?-AR agent isoproterenol caused substantial LD loss via activation of cytosolic lipases adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). ?-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 ?-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 ?-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 ?-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.

SUBMITTER: Schott MB

PROVIDER: S-EPMC5512075 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Schott Micah B MB Rasineni Karuna K Weller Shaun G SG Schulze Ryan J RJ Sletten Arthur C AC Casey Carol A CA McNiven Mark A MA

The Journal of biological chemistry 20170517 28

In liver steatosis (<i>i.e.</i> 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 ...[more]

PMID: 28515323

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Project description:BackgroundIndividuals with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high rates of relapse to drinking among abstinent individuals. Corticotropin-releasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following the application of the stress-associated neurotransmitter norepinephrine (NE) in a rat model of AUD.MethodsAdult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30 to 108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following the application of NE (10 μM) with and without the selective α1 adrenergic receptor (AR) antagonist prazosin (10 μM) or the α2AR antagonist atipamezole (10 μM). The experiments were performed using whole-cell patch clamp recordings in slices from CIE rats and air-exposed controls.ResultsNE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in amplitude of an evoked glutamatergic excitatory postsynaptic current (eEPSC). Both effects were sex- and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application only in stress-naïve males and this response was lost in stressed animals exposed to a 30-min restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males.ConclusionsNE exerts excitatory and inhibitory effects on CRF PVN PNCs, and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with the preapplication of prazosin. The selective blockade of α1AR may, therefore, ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.

Project description:Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Similarly, we found that BMAT in the tail vertebrae, but not the red marrow in the tibia, resists loss of neutral lipid with acute, 48-hour fasting in rats. The mechanisms underlying this phenomenon and its seemingly distinct regulation from peripheral white adipose tissue (WAT) remain unknown. To test the role of ?-adrenergic stimulation, a major regulator of adipose tissue lipolysis, we examined the responses of BMAT to ?-adrenergic agonists. Relative to inguinal WAT, BMAT had reduced phosphorylation of hormone sensitive lipase (HSL) after treatment with pan-?-adrenergic agonist isoproterenol. Phosphorylation of HSL in response to ?3-adrenergic agonist CL316,243 was decreased by an additional ~90% (distal tibia BMAT) or could not be detected (tail vertebrae). Ex vivo, adrenergic stimulation of lipolysis in purified BMAT adipocytes was also substantially less than iWAT adipocytes and had site-specific properties. Specifically, regulated bone marrow adipocytes (rBMAs) from proximal tibia and femur underwent lipolysis in response to both CL316,243 and forskolin, while constitutive BMAs from the tail responded only to forskolin. This occurred independently of changes in gene expression of ?-adrenergic receptors, which were similar between adipocytes from iWAT and BMAT, and could not be explained by defective coupling of ?-adrenergic receptors to lipolytic machinery through caveolin 1. Specifically, we found that whereas caveolin 1 was necessary to mediate maximal stimulation of lipolysis in iWAT, overexpression of caveolin 1 was insufficient to rescue impaired BMAT signaling. Lastly, we tested the ability of BMAT to respond to 72-hour treatment with CL316,243 in vivo. This was sufficient to cause beiging of iWAT adipocytes and a decrease in iWAT adipocyte cell size. By contrast, adipocyte size in the tail BMAT and distal tibia remained unchanged. However, within the distal femur, we identified a subpopulation of BMAT adipocytes that underwent lipid droplet remodeling. This response was more pronounced in females than in males and resembled lipolysis-induced lipid partitioning rather than traditional beiging. In summary, BMAT has the capacity to respond to ?-adrenergic stimuli, however, its responses are muted and BMAT generally resists lipid hydrolysis and remodeling relative to iWAT. This resistance is more pronounced in distal regions of the skeleton where the BMAT adipocytes are larger with little intervening hematopoiesis, suggesting that there may be a role for both cell-autonomous and microenvironmental determinants. Resistance to ?-adrenergic stimuli further separates BMAT from known regulators of energy partitioning and contributes to our understanding of why BMAT is preserved in states of fasting and caloric restriction.

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

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

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