Direct lysosome-based autophagy of lipid droplets in hepatocytes

Ryan J. Schulze, Eugene W. Krueger, Shaun G. Weller, Katherine M. Johnson, Carol A. Casey, Micah B. Schott, Mark A. McNiven

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelleselective form of this process (macrolipophagy) results in the engulfment of LDs within double-membrane delimited structures (autophagosomes) before lysosomal fusion. Whether this is an exclusive autophagic mechanism used by hepatocytes to catabolize LDs is unclear. It is also unknown whether lysosomes alonemight be sufficient to mediate LD turnover in the absence of an autophagosomal intermediate. We performed live-cell microscopy of hepatocytes to monitor the dynamic interactions between lysosomes and LDs in real-time. We additionally used a fluorescent variant of the LD-specific protein (PLIN2) that exhibits altered fluorescence in response to LD interactions with the lysosome. We find that mammalian lysosomes and LDs undergo interactions during which proteins and lipids can be transferred from LDs directly into lysosomes. Electron microscopy (EM) of primary hepatocytes or hepatocyte-derived cell lines supports the existence of these interactions. It reveals a dramatic process whereby the lipid contents of the LD can be "extruded" directly into the lysosomal lumen under nutrient-limited conditions. Significantly, these interactions are not affected by perturbations to crucial components of the canonical macroautophagy machinery and can occur in the absence of double-membrane lipoautophagosomes. These findings implicate the existence of an autophagicmechanism used bymammalian cells for the direct transfer of LD components into the lysosome for breakdown. This process further emphasizes the critical role of lysosomes in hepatic LD catabolism and provides insights into the mechanisms underlying lipid homeostasis in the liver.

Original languageEnglish (US)
Pages (from-to)32443-32452
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number51
DOIs
StatePublished - Dec 22 2020

Keywords

  • Hepatocyte
  • Lipid droplet
  • Lipolysis
  • Lysosome
  • Microautophagy

ASJC Scopus subject areas

  • General

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