Global loss of lysosomal acid lipase (LAL), as seen in lysosomal acid lipase deficiency (LAL-D), may cause significant liver proteome alterations in mice as opposed to hepatocyte-specific LAL loss, a study published in the Journal of Lipid Research suggests.

The researchers conducted comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL and mice with hepatocyte-specific LAL loss.

According to the study results, mice with systemic genetic loss of LAL had significant proteome alterations, including dysregulation of multiple proteins related to metabolism, inflammation, liver fibrosis, and cancer.

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Mice with systemic genetic loss of LAL also had impairments of both acidic and neutral lipase activity, leading to hepatic lipid accumulation and a complete metabolic shift in their livers.  

Read more about LAL-D etiology

The researchers discovered signs of hepatic inflammation and immune cell infiltration, with numerous upregulated inflammation-related gene ontology biological process terms.

In contrast, the liver proteome of both young and mature mice with hepatocyte-specific LAL loss was only mildly affected. It seems that the hepatocyte-specific deficiency of LAL does not phenocopy the metabolic alterations observed in mice globally lacking LAL. 

“These findings provide valuable insights into the mechanisms underlying liver dysfunction in LAL-D and may help in understanding why decreased LAL activity contributes to non-alcoholic fatty liver disease,” Bradić and colleagues noted.

“Previous studies in mouse models have focused primarily on specific metabolic alterations resulting from LAL-D. To our knowledge, the present study is the first to provide a comprehensive analysis of the effects of global and hepatocyte-specific LAL loss on the liver proteome.“

The lack of LAL leads to potentially fatal ectopic lysosomal lipid accumulation and contributes to the development of nonalcoholic fatty liver disease.

Reference

Bradić I, Liesinger L, Kuentzel KB, et al. Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase. J Lipid Res. Published online August 16, 2023. doi:10.1016/j.jlr.2023.100427

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