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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Bradić, I; Kuentzel, KB; Pirchheim, A; Rainer, S; Schwarz, B; Trauner, M; Larsen, MR; Vujić, N; Kratky, D.
From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism.
Biochim Biophys Acta Mol Cell Biol Lipids. 2024; 159575
Doi: 10.1016/j.bbalip.2024.159575
Web of Science
PubMed
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FullText_MUG
- Leading authors Med Uni Graz
- Bradic Ivan
- Kratky Dagmar
- Co-authors Med Uni Graz
- Küntzel Katharina Barbara
- Pirchheim Anita
- Rainer Silvia
- Schwarz Birgit
- Trauner Michael
- Vujic Nemanja
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- 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 (LALD). 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 and significant hepatic inflammation. 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. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.
- Find related publications in this database (Keywords)
- Lysosomal acid lipase deficiency
- Kupffer cell depletion
- Clodronate
- Metabolic dysfunction-associated steatotic liver
- disease
- Liver fibrosis