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bioRxiv · 10.1101/2024.12.08.627372

Ablation of sympathetic nerve-β3 adrenergic receptor-mediated adipose tissue lipolysis attenuates alcohol-induced liver injury in mice

Wickramasinghe, P.·Caron, A.·Eadha, S.·Parupalli, P.·Ganapavarapu, S.·Elmquist, J. K.·Liu, C.·Jia, L.
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Abstract

BACKGROUND & AIMSBinge drinking causes fat accumulation in the liver and is a known risk factor for more severe forms of alcohol-associated liver disease (ALD). Although adipocyte-released free fatty acids (FFA) have been shown to contribute to alcohol-induced liver damage, the signaling pathways that trigger lipolytic activity in adipose tissues following acute alcohol overconsumption is largely unknown. Notably, activation of sympathetic nerve-{beta}3 adrenergic receptor (ADRB3) plays a central role in sustained adipocyte lipolysis. However, whether this pathway is involved in acute alcohol-induced lipolysis remains unclear. We aimed to explore the effect of the sympathetic nerve-ADRB3-mediated pathway on adipocyte lipolytic action and fatty liver development following acute alcohol exposure. METHODSC57BL/6J mice were administered a single binge of alcohol to model acute alcohol exposure. 6-hydroxydopamine (6-OHDA) was injected systemically or locally to ablate sympathetic nerves. Mice lacking Adrb3 selectively in fat tissues (Adrb3FKO) were generated. White adipose tissue lipolysis, fatty liver development, and liver damage were investigated. RESULTSA single alcohol binge in C57BL/6J mice led to significant increases in white adipose tissue (WAT) norepinephrine (NE) content and plasma FFA levels, accompanied by the development of alcoholic hepatic steatosis. Acute alcohol-induced adipose tissue lipolysis and ALD were significantly mitigated by 6-OHDA-mediated systemic and fat tissue specific sympathetic nerve ablation. Deletion of Adrb3 in adipocytes protected mice from acute alcohol-induced adipose tissue lipolysis, hepatic fat accumulation, and liver injury. CONCLUSIONOur data indicate that binge drinking leads to the development of fatty liver and liver damage by activating adipose tissue sympathetic nerve-ADRB3-mediated lipolysis in mice. SUMMARYBinge drinking causes hepatic steatosis and liver injury through the activation of sympathetic nerve-{beta}3 adrenergic receptor-stimulated white adipose tissue lipolysis and release of free fatty acids. O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/627372v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@12ec139org.highwire.dtl.DTLVardef@8fa283org.highwire.dtl.DTLVardef@1f65d50org.highwire.dtl.DTLVardef@168344c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wickramasinghe, P., Caron, A., Eadha, S., Parupalli, P., Ganapavarapu, S., Elmquist, J. K., Liu, C., Jia, L.. 2024-12-10. Ablation of sympathetic nerve-β3 adrenergic receptor-mediated adipose tissue lipolysis attenuates alcohol-induced liver injury in mice. https://doi.org/10.1101/2024.12.08.627372

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