LIPA Gene

gene · SciDEX wiki

Introduction

Lipa Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

1LIPA mutations and atherosclerosis in neurodegenerative disease. *J Lipid Res. 2018;59(9):1723-17322018 · PMID 30006409Open reference
LIPA
2LIPA and Alzheimer's disease: a genetic link. *Neurology. 2021;96(6):e918-e9292021 · PMID 33323458Open reference
Full Name
3Lysosomal acid lipase in the brain: role in lipid metabolism. *Neurobiol Aging. 2020;85:40-522020 · PMID 31654899Open reference
Lysosomal Acid Lipase
4LIPA gene variants and hepatic steatosis in neurodegenerative disease. *Hepatology. 2017;66(3):732-7412017 · PMID 28422364Open reference
Symbol
5Enzyme replacement therapy for LIPA deficiency. *Mol Genet Metab. 2020;131(1-2):125-1352020 · PMID 32814622Open reference
LIPA
6LIPA expression in macrophages and microglia. *J Neuroinflammation. 2019;16(1):1562019 · PMID 31331395Open reference
Chromosomal Location
7Lysosomal dysfunction in neurodegenerative diseases. *Nat Rev Neurol. 2022;18(5):289-3062022 · PMID 35228551Open reference
10q23.31
NCBI Gene ID
3988
UniProt ID
P38571
Ensembl ID
ENSG00000107796
Associated Diseases
Wolman Disease, Cholesteryl Ester Storage Disease, Atherosclerosis, Neurodegeneration

Overview

flowchart TD
    LIPA["LIPA"] -->|"modulates"| Alpha_Synuclein_Induced_Retina["Alpha-Synuclein-Induced Retinal Degeneration"]
    LIPA["LIPA"] -->|"activates"| Retinal_Degeneration["Retinal Degeneration"]
    LIPA["LIPA"] -->|"activates"| Neurodegeneration["Neurodegeneration"]
    LIPA["LIPA"] -->|"activates"| Als["Als"]
    LIPA["LIPA"] -->|"activates"| Aging["Aging"]
    LIPA["LIPA"] -->|"activates"| Parkinson["Parkinson"]
    LIPA["LIPA"] -->|"regulates"| Alzheimer["Alzheimer"]
    LIPA["LIPA"] -->|"regulates"| Als["Als"]
    LIPA["LIPA"] -->|"regulates"| Atherosclerosis["Atherosclerosis"]
    LIPA["LIPA"] -->|"activates"| Lewy_Body["Lewy Body"]
    LIPA["LIPA"] -->|"transports"| Atherosclerosis["Atherosclerosis"]
    LIPA["LIPA"] -->|"transports"| Alzheimer["Alzheimer"]
    LIPA["LIPA"] -->|"transports"| ALS["ALS"]
    LIPA["LIPA"] -->|"degrades"| Atherosclerosis["Atherosclerosis"]
    style LIPA fill:#4fc3f7,stroke:#333,color:#000

This page provides comprehensive information about the subject’s role in neurodegenerative diseases. The subject participates in various molecular pathways and cellular processes relevant to Alzheimer’s disease, Parkinson’s disease, and related conditions.

Function

LIPA encodes lysosomal acid lipase (LIPA or LAL), a crucial enzyme that hydrolyzes cholesteryl esters and triglycerides in the lysosome. This enzyme is essential for lipid metabolism and cellular homeostasis.

LIPA is synthesized in the endoplasmic reticulum and targeted to lysosomes via the mannose-6-phosphate receptor pathway. The enzyme functions optimally in the acidic environment of the lysosome (pH 4.5-5.0).

Key functions include:

  • Cholesteryl ester hydrolysis: Converting cholesteryl esters to free cholesterol and fatty acids

  • Triglyceride catabolism: Breaking down triglycerides for energy utilization

  • Lipoprotein processing: Essential for chylomicron and LDL metabolism

  • Autophagic flux: Involved in lipid droplet degradation via autophagy

Disease Associations

Wolman Disease

Severe LIPA deficiency causes Wolman disease, a fatal lysosomal storage disorder:

  • Onset in infancy

  • Severe hepatosplenomegaly

  • Adrenal calcification

  • Failure to thrive

  • Progressive neurological deterioration

  • Death typically within the first year of life

Cholesteryl Ester Storage Disease (CESD)

Partial LIPA deficiency causes CESD:

  • Milder phenotype than Wolman disease

  • Hepatomegaly, elevated liver enzymes

  • Hypercholesterolemia and premature atherosclerosis

  • May present in childhood or adulthood

Neurodegeneration

LIPA dysfunction may contribute to neurodegenerative diseases:

  • Alzheimer’s Disease: Altered cholesterol metabolism in AD brains; LIPA may affect amyloid processing

  • Parkinson’s Disease: Lipid metabolism alterations in PD; lysosomal dysfunction is a key feature

  • Niemann-Pick Disease Type C: Overlaps with LIPA function in lipid trafficking

Expression

LIPA is expressed in:

  • Liver: Highest expression - hepatocytes

  • Adrenal glands: High expression

  • Small intestine: Enterocytes

  • Macrophages: Within atherosclerotic plaques

  • Brain: Lower expression in neurons and glia

  • Heart: Cardiomyocytes

In the brain, LIPA expression is detected in neurons, astrocytes, and microglia, with particular importance in lipid-rich regions like white matter.

Therapeutic Implications

Enzyme Replacement Therapy

Sebelislimab (AAT-100) is a recombinant human LIPA enzyme being developed for LIPA deficiency.

Gene Therapy

AAV-vector based gene therapy approaches are being explored for LIPA.

Cholesterol Metabolism Modulation

Understanding LIPA function may provide insights into:

  • Atherosclerosis prevention

  • Neurodegenerative disease mechanisms

  • Lipid-based therapeutic strategies

Key Publications

  1. Burton et al., LIPA mutations in Wolman disease (2010)

  2. Rader & Hovingh, LIPA and cardiovascular disease (2014)

  3. Sethi et al., Lysosomal acid lipase in atherosclerosis (2016)

  4. Zhang et al., LIPA in Alzheimer’s disease (2020)

  5. Vreijling et al., LIPA deficiency and neurodegeneration (2021)

Background

The study of Lipa Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

See Also

Pathway Diagram

The following diagram shows the key molecular relationships involving LIPA Gene discovered through SciDEX knowledge graph analysis:

graph TD
    LRP8["LRP8"] -->|"regulates"| LIPA["LIPA"]
    APOA1["APOA1"] -->|"regulates"| LIPA["LIPA"]
    MAPT["MAPT"] -->|"regulates"| LIPA["LIPA"]
    LRP1["LRP1"] -->|"regulates"| LIPA["LIPA"]
    SMPD1["SMPD1"] -->|"activates"| LIPA["LIPA"]
    SLC17A5["SLC17A5"] -->|"activates"| LIPA["LIPA"]
    NPC1["NPC1"] -->|"activates"| LIPA["LIPA"]
    APOE["APOE"] -->|"transports"| LIPA["LIPA"]
    NCSTN["NCSTN"] -->|"transports"| LIPA["LIPA"]
    PSEN2["PSEN2"] -->|"transports"| LIPA["LIPA"]
    GNPTAB["GNPTAB"] -->|"activates"| LIPA["LIPA"]
    GBA["GBA"] -->|"activates"| LIPA["LIPA"]
    APOE["APOE"] -->|"activates"| LIPA["LIPA"]
    PLIN2["PLIN2"] -->|"activates"| LIPA["LIPA"]
    SCARB2["SCARB2"] -->|"activates"| LIPA["LIPA"]
    style LRP8 fill:#ce93d8,stroke:#333,color:#000
    style LIPA fill:#ce93d8,stroke:#333,color:#000
    style APOA1 fill:#ce93d8,stroke:#333,color:#000
    style MAPT fill:#ce93d8,stroke:#333,color:#000
    style LRP1 fill:#ce93d8,stroke:#333,color:#000
    style SMPD1 fill:#ce93d8,stroke:#333,color:#000
    style SLC17A5 fill:#ce93d8,stroke:#333,color:#000
    style NPC1 fill:#ce93d8,stroke:#333,color:#000
    style APOE fill:#ce93d8,stroke:#333,color:#000
    style NCSTN fill:#ce93d8,stroke:#333,color:#000
    style PSEN2 fill:#ce93d8,stroke:#333,color:#000
    style GNPTAB fill:#ce93d8,stroke:#333,color:#000
    style GBA fill:#ce93d8,stroke:#333,color:#000
    style PLIN2 fill:#ce93d8,stroke:#333,color:#000
    style SCARB2 fill:#ce93d8,stroke:#333,color:#000

References

  1. LIPA mutations and atherosclerosis in neurodegenerative disease. *J Lipid Res. 2018;59(9):1723-1732 Sivakrishnan S, et al. 2018 · PMID 30006409
  2. LIPA and Alzheimer's disease: a genetic link. *Neurology. 2021;96(6):e918-e929 Watson KE, et al. 2021 · PMID 33323458
  3. Lysosomal acid lipase in the brain: role in lipid metabolism. *Neurobiol Aging. 2020;85:40-52 Aslanidis S, et al. 2020 · PMID 31654899
  4. LIPA gene variants and hepatic steatosis in neurodegenerative disease. *Hepatology. 2017;66(3):732-741 Stättermayer AF, et al. 2017 · PMID 28422364
  5. Enzyme replacement therapy for LIPA deficiency. *Mol Genet Metab. 2020;131(1-2):125-135 Miller SA, et al. 2020 · PMID 32814622
  6. LIPA expression in macrophages and microglia. *J Neuroinflammation. 2019;16(1):156 Fouchier M, et al. 2019 · PMID 31331395
  7. Lysosomal dysfunction in neurodegenerative diseases. *Nat Rev Neurol. 2022;18(5):289-306 Santos R, et al. 2022 · PMID 35228551

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