Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies

Current Opinion in Lipidology - Tập 29 Số 3 - Trang 218-223 - 2018
Hanrui Zhang1,2,3,4
1Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA
2e-mail: [email protected]
3fax: +1 212 305 3213
4to Hanrui Zhang, MB, PhD, Division of Cardiology, Department of Medicine, Columbia University Medical Center, 630 West 168th Street, PS10-401, New York, NY 10032, USA. Tel: +1 212 305 3508

Tóm tắt

Purpose of reviewLysosomal acid lipase (LAL), encoded by theLIPAgene, 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 ofLIPAas a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency.Recent findingsThe essential role of LAL in lipid metabolism has been confirmed in human and mice with LAL deficiency. In humans, loss-of-function mutations ofLIPAcause 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 identifiedLIPAas a risk locus for CHD, but the causal variants and mechanisms remain to be determined.SummaryDespite 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.

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