Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation

Maidina Tuohetahuntila, Martijn R. Molenaar, Bart Spee, Jos F. Brouwers, Richard Wubbolts, Martin Houweling, Cong Yan, Hong Du, Brian C. VanderVen, Arie B. Vaandrager, J. Bernd Helms

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19 Scopus citations

Abstract

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 -smooth muscle actin (-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.

Original languageEnglish (US)
Pages (from-to)12436-12448
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number30
DOIs
StatePublished - Jul 21 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tuohetahuntila, M., Molenaar, M. R., Spee, B., Brouwers, J. F., Wubbolts, R., Houweling, M., Yan, C., Du, H., VanderVen, B. C., Vaandrager, A. B., & Helms, J. B. (2017). Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation. Journal of Biological Chemistry, 292(30), 12436-12448. https://doi.org/10.1074/jbc.M117.778472