PURPOSE OF REVIEW: Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an 
essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride 
delivered to the lysosome. This review highlights the novel pathophysiological 
role of LAL, the functional genomic discoveries of LIPA as a risk locus for 
coronary heart diseases (CHD), and the clinical advance in therapies for LAL 
deficiency.
RECENT FINDINGS: The essential role of LAL in lipid metabolism has been 
confirmed in human and mice with LAL deficiency. In humans, loss-of-function 
mutations of LIPA cause rare lysosomal disorders, Wolman disease, and 
cholesteryl ester storage disease, in which LAL enzyme replacement therapy has 
shown significant benefits in a phase 3 clinical trial. Recent studies have 
revealed the role of LAL-mediated lysosomal lipolysis in regulating macrophage 
M2 polarization, lipid mediator production, VLDL secretion, lysosomal function 
and autophagy, extracellular degradation of aggregated-LDL, and adipose tissue 
lipolysis. Genome-wide association studies and functional genomic studies have 
identified LIPA as a risk locus for CHD, but the causal variants and mechanisms 
remain to be determined.
SUMMARY: Despite years of research, our understanding of LAL is incomplete. 
Future studies will continue to focus on the key pathophysiological functions of 
LAL in health and diseases including CHD.