Researchers from the University Medical Center Hamburg-Eppendorf, Germany, identified a pathway involving lysosomal acid lipase (LAL) in endothelial cells that could be relevant in the context of human LAL deficiency (LAL-D).

In a commentary paper published in Adipocyte, the researchers explained that loss of LAL in endothelial cells impaired endothelial proliferation and decreased thermogenic adaptation of brown adipose tissue (BAT) and white adipose tissue (WAT).

LAL was expressed at high levels in endothelial cells of BAT and WAT, and its expression in endothelial cells was higher compared with that observed in adipocytes. Moreover, LAL expression was induced by cold activation.


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Experiments in endothelial cell-specific LAL knockout mice revealed decreased thermogenic capacity of both BAT and WAT. The researchers observed insufficient uptake of triglycerides and glucose, as well as a downregulated thermogenic marker and the reduced appearance of beige adipocytes.

Read more about LAL-D etiology

In addition, analysis of the vascular bed in thermogenic adipose tissues of LAL-deficient mice revealed reduced expression of endothelial marker genes and proteins in response to cold exposure. Vascular density was also diminished.

The researchers confirmed that cold-induced endothelial proliferation required LAL-mediated triglyceride-rich lipoprotein (TRL) processing, although the underlying mechanism was not fully elucidated.

Cultured human human umbilical vein endothelial cells and adipocyte precursor cells showed increased proliferation when incubated with human TRL particles. This pro-proliferative effect was mediated by LAL and was dependent on the activation of hypoxia-induced factor. “Mechanistically, cell culture experiments indicate that LAL-mediated TRL processing leads to the generation of reactive oxygen species, which in turn activate HIF-mediated proliferative responses,” the researchers explained.

Future studies are needed to confirm the presence of such pathway in humans, as well as its physiological relevance. Furthermore, the analysis of transcriptional and functional changes in endothelial cells of oxidative tissues from patients with LAL-D would be important to understand the relevance of this pathway to LAL-D pathogenesis.

Reference

Fischer AW, Jaeckstein MY, Heeren J. Lysosomal acid lipase promotes endothelial proliferation in cold-activated adipose tissue. Adipocyte. 2022;11(1):28-33. doi:10.1080/21623945.2021.2013416