Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol levels and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (LAL), encoded by the gene LIPA, which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet would prevent the development of NAFLD. As expected, mice fed the Western diet exhibited numerous markers of NAFLD, including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the Western diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Overall, we found that hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD, suggesting that targeting LAL expression may not be a viable route to treat NAFLD in humans.

Original languageEnglish (US)
Article number100133
JournalJournal of lipid research
Volume62
Early online dateOct 5 2021
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
The authors thank the University of Minnesota Research Animal Facility staff for animal care, Colleen F?rster for her assistance with histology preparation, the University of Minnesota Genomics Core for performing RNA-Seq, the University of Minnesota Informatics Institute (Dr Juan Abrahante) for RNA-Seq analysis, and the University of Minnesota University Imaging Centers (Dr Gail Celio, SCR_020997) for electron microscope sample preparation and imaging. All viral vectors used in this study were generated by the University of Minnesota Viral Vector and Cloning Core (Minneapolis, MN). We also thank Mara Mashek for help with viral injections and mouse care. This work was supported by the American Diabetes Association (1-16-IBS-203) and the National Institutes of Health (5T32AG029796-13, R01AG055452, R01DK020593, R01DK108790, R01DK114401, and R01DK122056). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The authors thank the University of Minnesota Research Animal Facility staff for animal care, Colleen Förster for her assistance with histology preparation, the University of Minnesota Genomics Core for performing RNA-Seq, the University of Minnesota Informatics Institute (Dr Juan Abrahante) for RNA-Seq analysis, and the University of Minnesota University Imaging Centers (Dr Gail Celio, SCR_020997) for electron microscope sample preparation and imaging. All viral vectors used in this study were generated by the University of Minnesota Viral Vector and Cloning Core (Minneapolis, MN). We also thank Mara Mashek for help with viral injections and mouse care. This work was supported by the American Diabetes Association (1-16-IBS-203) and the National Institutes of Health (5T32AG029796-13, R01AG055452, R01DK020593, R01DK108790, R01DK114401, and R01DK122056). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords

  • Autophagy
  • Cholesterol/cell and tissue
  • Dietary fat
  • Immune infiltration
  • Inflammation
  • Lipase/hepatic
  • Liver
  • Lysosomal acid lipase
  • NAFLD

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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