Lanifibranor reduces inflammation and improves dyslipidemia in lysosomal acid lipase-deficient mice

Background and Aims Recent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy (ERT), however, liver histolopathology improved in some but not all patients. We hypothesized that the pan-PPAR agonist lanifibranor may have beneficial effects on liver inflammation in LAL knockout (Lal-/-) mice based on its promising results in alleviating liver inflammation in patients with metabolic dysfunction-associated steatohepatitis. Methods Female Lal-/- mice were daily gavaged with lanifibranor or vehicle for 21 days. The effects of the treatment were assessed by measuring body and organ weights, plasma lipids and lipoproteins, as well as hematological parameters, followed by liver proteomics and metabolomics. Results Lanifibranor treatment slightly altered organ weights without affecting the total body weight of Lal-/- mice. We observed major changes in the proteome, with multiple proteins related to lipid metabolism, peroxisomal, and mitochondrial activities being upregulated and inflammation-related proteins being downregulated in the livers of treated mice. Hepatic lipid levels and histology remained unaltered, whereas plasma triacylglycerol and total cholesterol levels were decreased and the lipoprotein profile of lanifibranor-treated Lal-/- mice improved. Conclusions Lanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal-/- mice. These findings suggest the necessity of a further combined study of lanifibranor with ERT in Lal-/- mice to improve the phenotype. Moreover, there is a compelling rationale for conducting clinical trials to assess the efficacy of lanifibranor as a potential treatment option for LAL-D in humans.