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

Michael W Lopresti,Wenqi Cui,Breann E Abernathy,Gavin Fredrickson,Fanta Barrow,Arnav S Desai,Xavier S Revelo,Douglas G Mashek

doi:10.1016/j.jlr.2021.100133

Michael W Lopresti, Wenqi Cui + Show 6 more

Open Access

https://doi.org/10.1016/j.jlr.2021.100133

Copy DOI

Journal: Journal of lipid research	Publication Date: Jan 1, 2021
Citations: 8	License type: cc-by

Affiliation: University of Minnesota

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.

Highlights

Supplementary key words cholesterol/cell and tissue dietary fat inflammation lipase/hepatic liver nonalcoholic fatty liver disease (NAFLD) lysosomal acid lipase autophagy immune infiltration
As the dysregulation of lipid metabolism is a driving force in NAFLD, we examined whether the hepatic overexpression of human LIPA could protect mice from developing NAFLD on a Western diet
The FPC diet significantly increased the percent of total area stained by Oil Red O, though this was unaffected by lysosomal acid lipase (LAL) expression (Fig. 1H and supplemental Fig. S1F)

Summary

Introduction

Histological staining of livers revealed variations in fat accumulation and LD populations across groups resulting from both LAL overexpression and the FPC diet (Fig. 1G–I and supplemental Fig. S1E–G). Measurements of total hepatic lipids further confirm that the hepatomegaly is largely the result of lipid accumulation in mice on the FPC diet and was unaltered by LAL expression in both males (Fig. 2A) and females (supplemental Fig. S3A).

Results

Conclusion