From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL-D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver without significantly affecting liver injury. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. The results suggest that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver, and KC depletion further aggravates hepatic CE levels and dyslipidemia, a finding also supported by our proteomics analysis.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Ivan Bradić  

LAB HEAD: Dagmar Kratky

PROVIDER: PXD056343 | Pride | 2024-12-01

REPOSITORIES: Pride