In patients with lysosomal acid lipase deficiency (LAL-D), infiltrating macrophages appear to play a key role in the pathogenesis of the disease, according to findings from an experimental analysis published in the journal Molecular Metabolism.
Currently, LAL is the only enzyme shown to hydrolyze triacylglycerols, diacylglycerols, cholesteryl esters, and retinyl esters, in order to release fatty acids, monoacylglycerols, free cholesterol, and retinol. These products are subsequently secreted or used by the cell for membrane assembly, energy production, signaling purposes, or steroidogenesis. The process is observed in enterocytes as well, in which nascent lipid droplets are scavenged from the endoplasmic reticulum mere minutes following absorption of dietary lipids and then sent to the lysosome for lipid degradation.
One of the main pathologic characteristics of LAL-D is known to be lipid malabsorption in the small intestine, along with macrophage infiltration; however, the exact role played by LAL in intestinal lipid metabolism remains to be elucidated.
The researchers sought to explore this role with using 2 types of mice: (1) global LAL-deficient (LAL knockout [KO]) mice and (2) KO mice that lacked the enzyme observed exclusively in enterocytes (iLAL KO)—also known as mice with an intestine-specific deletion of LAL. They obtained 3 parts of the small intestine—that is, the duodenum, the jejunum, and the ileum—from LAL KO mice, iLAL KO mice, and corresponding controls.
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The following methods were used in the investigation:
- Plasma and tissue lipid analysis
- Energy metabolism in vivo
- Histology, immunohistochemistry, and oil red staining
- Chylomicron secretion
- Isolation of enterocytes
- Cholesteryl ester and triacylglycerol hydrolase activity assays
- Electron microscopy
- Bis(monoacylglycerol)phosphate analysis
- Isolation and labeling of very-low-density lipoprotein cholesterol with [3H]-triolein
- Basolateral lipid uptake
- Fecal lipid extraction
- Western blotting analysis
- RNA isolation and quantitative real-time PCR
Results of the study revealed that beside prominent lipid accumulation in macrophages of the lamina propria of the small intestine, as previously reported, lipid-containing lysosomes in duodenal enterocytes of iLAL KO mice were seen, thus indicating that enterocyte LAL may play a key role in metabolism of dietary lipids. Other findings included the following:
- Enterocyte-specific LAL deficiency affects neither body weight nor circulating lipid concentrations;
- Massive lipid-rich macrophage infiltration was observed in the lamina propria of LAL KO mice but not those of
iLAL KO mice;
- LAL KO mice absorb fewer dietary lipids; however, they exhibit accelerated basolateral lipid uptake, secrete fewer chylomicrons, and have increased loss of fecal lipids;
- Genes and inflammatory markers involved in lipid metabolism were overexpressed in the duodenum of old, but not younger, LAL KO mice; and
- Global LAL deficiency, but not intestinal LAL deficiency, impacts intestinal lipid metabolism and inflammation.
Despite the significant reduction of LAL activity in enterocytes of iLAL KO mice, “villous morphology, intestinal lipid concentrations, expression of lipid transporters and inflammatory genes, as well as lipoprotein secretion[,] were comparable to control mice,” the researchers explained. “Our results demonstrate that loss of LAL solely in enterocytes is not a sufficient trigger to replicate the severe intestinal phenotype observed in global LAL KO mice,” they concluded.
Bianco V, Korbelius M, Vujic N, et al. Impact of (intestinal) LAL deficiency on lipid metabolism and macrophage infiltration. Mol Metab. Published online May 12, 2023. doi:10.1016/j.molmet.2023.101737