Lysosomal acid lipase promotes endothelial proliferation in cold-activated adipose tissue

Oxidative tissues such as brown adipose tissue and muscle internalize large amounts of circulating lipids and glucose as energy source. Endothelial cells (ECs) provide a platform for regulated transport and processing of blood-borne nutrients. Next to this role, it has become recognized that intercellular crosstalk between ECs and underlying parenchymal cells is indispensable for maintenance of tissue homoeostasis. Here, we comment on our recent observation that capillary ECs in thermogenic adipose tissues take up and metabolize entire triglyceride-rich lipoprotein (TRL) particles in response to cold exposure. This process is dependent on CD36, lipoprotein lipase (LPL) and lysosomal acid lipase (LAL). Remarkably, loss of LAL specifically in endothelial cells results in impaired endothelial proliferation and diminished thermogenic adaptation. Mechanistically, cell culture experiments indicate that LAL-mediated TRL processing leads to the generation of reactive oxygen species, which in turn activate hypoxia-induced factor (HIF)-mediated proliferative responses. In the current manuscript, we provide in vivo evidence that LAL-deficiency impairs proliferation of endothelial cells in thermogenic adipose tissue. In addition, we show uptake of nanoparticle-labelled TRL and LAL expression in cardiac endothelial cells, suggesting a physiological function of endothelial lipoprotein processing not only in thermogenic adipose tissue but also in cardiac muscle.

Automated summary

Endothelial cells play a crucial role in the transport and processing of circulating nutrients and maintenance of tissue homeostasis. Recent studies have shown that capillary endothelial cells in thermogenic adipose tissues take up and metabolize triglyceride-rich lipoprotein particles in response to cold exposure, and this process is dependent on specific proteins and enzymes. Loss of lysosomal acid lipase in endothelial cells leads to impaired endothelial proliferation and diminished thermogenic adaptation. The processing of lipoproteins by lysosomal acid lipase generates reactive oxygen species, which in turn activate proliferative responses mediated by hypoxia-induced factor. This study provides in vivo evidence for the importance of lysosomal acid lipase in endothelial cells of thermogenic adipose tissue.