Hepatic stellate cell (HSC) activation occurs along with decreased Perilipin5 (Plin5) and liver fatty acid-binding protein (L-Fabp) expression and coincident lipid droplet (LD) depletion. Conversely, the activated phenotype is reversible in WT HSCs upon forced expression of Plin5. Here, we asked if L-Fabp expression is required for Plin5-mediated rescue of the quiescent phenotype. Lentiviral Plin5 transduction of passaged L-Fabp-/- HSCs failed to reverse activation markers or restore lipogenic gene expression and LD formation. However, adenoviral L-Fabp infection of lentiviral Plin5 transduced L-Fabp-/- HSCs restored both the quiescent phenotype and LD formation, an effect also mediated by adenoviral intestine-Fabp or adipocyte-Fabp. Expression of exogenous Plin5 in activated WT HSCs induced a transcriptional program of lipogenic gene expression including endogenous L-Fabp, but none of the other FABPs. We further demonstrated that selective, small molecule inhibition of endogenous L-Fabp also eliminated the ability of exogenous Plin5 to rescue LD formation and reverse activation of WT HSCs. This functional coordination of L-Fabp with Plin5 was 5′-AMP-activated protein kinase (AMPK)-dependent and was eliminated by AMPK inhibition. Taken together, our results indicate that L-Fabp is required for Plin5 to activate a transcriptional program that restores LD formation and reverses HSC activation.
Bibliographical noteFunding Information:
This work was supported by the Doisy Research Fund and a Research Award from the Saint Louis University Liver Center (to A. C.). N.O.D. was supported by grants from the National Institutes of Health (HL-38180, DK-112378, DK-56260, DK-52574, Murine and Advanced Imaging Cores). This work was also supported by grants from the National Institutes of Health, the Wisconsin Alumni Research Foundation (WARF), and the University of Wisconsin Institute for Clinical and Translational Research (ICTR; to A.D.A. and M.P.K.) W.S.B. was supported by grants from the National Institutes of Health (RO1 DK-068437 and RO1 DK-101251). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Manuscript received 3 May 2017 and in revised form 7 December 2017. Published, JLR Papers in Press, January 9, 2018 DOI https://doi.org/10.1194/jlr.M077487
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