Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation.
| Autor: | Tuohetahuntila M; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Molenaar MR; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Spee B; Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Brouwers JF; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Wubbolts R; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Houweling M; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Yan C; Indiana University School of Medicine, Indianapolis, Indiana 46202., Du H; Indiana University School of Medicine, Indianapolis, Indiana 46202., VanderVen BC; Department of Microbiology and Immunology, Cornell University, C5 181 Veterinary Medicine Center, Ithaca, New York 14853., Vaandrager AB; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands., Helms JB; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands. Electronic address: J.B.Helms@uu.nl. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2017 Jul 28; Vol. 292 (30), pp. 12436-12448. Date of Electronic Publication: 2017 Jun 14. |
| DOI: | 10.1074/jbc.M117.778472 |
| Abstrakt: | Activation of hepatic stellate cells (HSCs) is a critical step in the development of liver fibrosis. During activation, HSCs lose their lipid droplets (LDs) containing triacylglycerols (TAGs), cholesteryl esters, and retinyl esters (REs). We previously provided evidence for the presence of two distinct LD pools, a preexisting and a dynamic LD pool. Here we investigate the mechanisms of neutral lipid metabolism in the preexisting LD pool. To investigate the involvement of lysosomal degradation of neutral lipids, we studied the effect of lalistat, a specific lysosomal acid lipase (LAL/Lipa) inhibitor on LD degradation in HSCs during activation in vitro The LAL inhibitor increased the levels of TAG, cholesteryl ester, and RE in both rat and mouse HSCs. Lalistat was less potent in inhibiting the degradation of newly synthesized TAG species as compared with a more general lipase inhibitor orlistat. Lalistat also induced the presence of RE-containing LDs in an acidic compartment. However, targeted deletion of the Lipa gene in mice decreased the liver levels of RE, most likely as the result of a gradual disappearance of HSCs in livers of Lipa -/- mice. Lalistat partially inhibited the induction of activation marker α-smooth muscle actin (α-SMA) in rat and mouse HSCs. Our data suggest that LAL/Lipa is involved in the degradation of a specific preexisting pool of LDs and that inhibition of this pathway attenuates HSC activation. (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.) |
| Databáze: | MEDLINE |
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