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Lysosomal lipase

From Wikipedia, the free encyclopedia

LIPA
Identifiers
AliasesLIPA, CESD, LAL, lipase A, lysosomal acid type
External IDsOMIM: 613497; MGI: 96789; GeneCards: LIPA
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
3.1.1.13↗↗↗↗
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

3988

16889

Ensembl

ENSG00000107798

ENSMUSG00000024781

UniProt

P38571

Q9Z0M5

RefSeq (mRNA)

NM_000235
NM_001127605
NM_001288979

NM_001111100
NM_021460

RefSeq (protein)

NP_000226
NP_001121077
NP_001275908

NP_001104570
NP_067435

Location (UCSC)Chr 10: 89.21 – 89.41 MbChr 19: 34.47 – 34.5 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Lysosomal lipase (also called lipase A) is an enzyme which in humans is encoded by the gene LIPA.[5] As a lipase, Lysosomal lipase helps break down fats like triglycerides by removing fatty acids.[6] Notably, it can also act as a sterol esterase, meaning it is able to remove fatty acids attached to cholesterol molecules (as part of cholesteryl esters).[6] As its name suggests, it is located in lysosomes, which are organelles inside of cells which function to break down large molecules like proteins, carbohydrates, and lipids. Alternatively spliced transcript variants have been found for this gene.[5]

Function

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This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides, leading to the production of free cholesterol and fatty acids.[7] Notably, LAL is the only known acid lipase that hydrolyzes cholesteryl esters and triglycerides within the lysosomal environment.[7][8]

LAL is essential to intracellular lipid metabolism in macrophages and hepatocytes. Upon uptake of LDL by endocytosis, cholesteryl esters and triglycerides are transported to lysosomes where they are hydrolyzed by LAL.[9] The resulting free cholesterol either exits the lysosome for future use in membrane synthesis or is re-esterified in the endoplasmic reticulum by ACAT to form lipid droplets.[9] This process is important for foam cell formation during atherogenesis.[10]

Lysosomal lipases function optimally at an acidic pH which are complementary with the environment found in the lysosomal lumen.[11] These enzymes were believed to only hydrolyze the lipids found in organelle membranes and extracellular lipids. However, recent studies suggest that lysosomal lipases also play a significant role in the degradation of cytosolic lipids, a characteristic that was previously limited to neutral lipases.[11] The ability of the lysosome to degrade a diverse set of cargo is attributed to the lysosomal lipase and other soluble hydrolases. These enzymes include sulphatases, phosphatases, peptidases, glycosidases, and nucleases.[12]

The biochemical role of these enzymes are observed in various pathways, specifically in lipid catabolism. At the intracellular level, the byproducts released by the lysosomal lipase are recycled for membrane assembly and energy production.[13] In addition, these enzymes participate in the production of specific fatty acids necessary for the metabolic reprogramming of CD8+ memory T cells, macrophage alternative activation, and lipid mediator synthesis.[13] As observed, the degradation of these lipids are essential to maintain homeostasis within the body. The absence or decreased activity of this enzyme could lead to various metabolic disorders.[12]

Clinical significance

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Mutations in the LIPA gene that cause loss-of-function can result in infant-onset Wolman disease, caused by a complete lack of LAL production, or a later-onset Cholesterol ester storage disease (CESD), caused by a 5-10% reduction in LAL production.[7]

Chlorpromazine is an inhibitor of lysosomal lipase.[14]

A genome wide survey suggests that lysosomal lipase A (located at chromosome 10q23.31) is associated with coronary artery disease in humans.[15] LAL was found to have high expression in macrophages located in atherosclerotic plaques, where its activity contributes to the accumulation of lipid droplets and the progression of plaque development.[7][10]

Schematic overview of LAL function in lipid metabolism. LDL is hydrolyzed by LAL in the lysosome, producing free cholesterol, which either leaves the cell or is re-esterified in the endoplasmic reticulum by ACAT to form lipid droplets, the foundation of foam cells.[9]

References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000107798 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024781 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: Lipase A, lysosomal acid type". Retrieved 2018-08-22.
  6. 1 2 "P38571 · LICH_HUMAN". uniprot.org. UniProt consortium. Retrieved 2026-08-06.
  7. 1 2 3 4 Li F, Zhang H (May 2019). "Lysosomal Acid Lipase in Lipid Metabolism and Beyond". Arteriosclerosis, Thrombosis, and Vascular Biology. 39 (5): 850–856. doi:10.1161/atvbaha.119.312136. PMC 6482091. PMID 30866656.
  8. ↑ Ding HR, Wang JL, Ren HZ, Shi XL (2018). "Lipometabolism and Glycometabolism in Liver Diseases". BioMed Research International. 2018 1287127. doi:10.1155/2018/1287127. PMC 6530156. PMID 31205932.
  9. 1 2 3 Dubland JA, Francis GA (2015). "Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism". Frontiers in Cell and Developmental Biology. 3 3. doi:10.3389/fcell.2015.00003. PMC 4313778. PMID 25699256.
  10. 1 2 Bobryshev YV, Ivanova EA, Chistiakov DA, Nikiforov NG, Orekhov AN (2016). "Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis". BioMed Research International. 2016 9582430. doi:10.1155/2016/9582430. PMC 4967433. PMID 27493969.
  11. 1 2 Cuervo AM (June 2013). "Preventing lysosomal fat indigestion". Nature Cell Biology. 15 (6): 565–567. doi:10.1038/ncb2778. PMID 23728462. S2CID 11119477.
  12. 1 2 Settembre C, Fraldi A, Medina DL, Ballabio A (May 2013). "Signals from the lysosome: a control centre for cellular clearance and energy metabolism". Nature Reviews. Molecular Cell Biology. 14 (5): 283–296. doi:10.1038/nrm3565. PMC 4387238. PMID 23609508.
  13. 1 2 Zhang H (June 2018). "Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies". Current Opinion in Lipidology. 29 (3): 218–223. doi:10.1097/MOL.0000000000000507. PMC 6215475. PMID 29547398.
  14. ↑ Sauro VS, Klamut HJ, Lin CH, Strickland KP (1985). "Lysosomal triacylglycerol lipase activity in L6 myoblasts and its changes on differentiation". The Biochemical Journal. 227 (2): 583–589. doi:10.1042/bj2270583. PMC 1144878. PMID 4004781.
  15. ↑ Wild PS, Zeller T, Schillert A, Szymczak S, Sinning CR, Deiseroth A, et al. (August 2011). "A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease". Circulation. Cardiovascular Genetics. 4 (4): 403–412. doi:10.1161/CIRCGENETICS.110.958728. PMC 3157552. PMID 21606135.{{cite journal}}: CS1 maint: deprecated archival service (link)

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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