Fasn 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.
[^1]
| **FASN Gene** | | [^2]
|---|---| [^3]
| **Full Name** | Fatty Acid Synthase | [^4]
| **Symbol** | FASN | [^5]
| **Chromosome** | 1q25 | [^6]
| **NCBI Gene ID** | 2194 | [^7]
| **OMIM** | 600005 | [^8]
| **Ensembl ID** | ENSG00000169710 | [^9]
| **UniProt** | P49327 |
| **Associated Diseases** | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Metabolic Disorders, Cancer |
The FASN gene encodes fatty acid synthase (FASN), a crucial metabolic enzyme that catalyzes the de novo synthesis of long-chain fatty acids. Located on chromosome 1q25, FASN is one of the largest enzyme complexes in cellular metabolism, functioning as a type I fatty acid synthase that performs all catalytic steps in fatty acid synthesis within a single polypeptide [1].
FASN is particularly significant in the context of neurodegenerative diseases because brain lipid metabolism is essential for neuronal function, membrane maintenance, and myelin synthesis. Dysregulation of FASN has been implicated in Alzheimer's disease, Parkinson's disease, and various metabolic disorders affecting the central nervous system [2].
¶ Gene Structure and Function¶ Catalytic DomainsThe FASN protein contains multiple functional domains arranged in a linear array:
β-ketoacyl synthase (KS) domain : Initiates fatty acid chain condensationMalonyl/acetyltransferase (MAT) domain : Transfers acyl groupsβ-hydroxyacyl dehydratase (DH) domain : Removes water moleculesEnoyl reductase (ER) domain : Reduces double bondsβ-ketoacyl reductase (KR) domain : Reduces β-keto groupsAcyl carrier protein (ACP) domain : Carries the growing fatty acid chain
FASN catalyzes the synthesis of palmitate (C16:0) as its primary product from simpler precursors:
Primary substrate : Acetyl-CoA (primer) and malonyl-CoA ( extender)Cofactors required : NADPH (reducing power)Final product : Palmitate (16-carbon saturated fatty acid)Reaction stoichiometry : 8 acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+ → palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
In the central nervous system, FASN plays several important roles [3]:
De novo lipogenesis : Synthesis of fatty acids for membrane phospholipidsMyelin maintenance : Supplying lipids for myelin sheath integritySynaptic vesicle formation : Providing lipids for neurotransmitter releaseLipid droplet formation : Energy storage in neurons and glia
FASN expression in the brain:
Neurons Astrocytes Oligodendrocytes : Essential for myelin lipid synthesisMicroglia
FASN dysregulation is increasingly recognized in AD pathophysiology:
Upregulation in AD brain : FASN expression is elevated in AD hippocampus and cortex Amyloid interaction : FASN activity may influence APP processing and Aβ generationLipid homeostasis disruption : Altered fatty acid metabolism contributes to membrane abnormalitiesMitochondrial dysfunction : FASN-derived lipids affect mitochondrial functionNeuroinflammation : Lipid mediators from FASN modulate glial activation
The relationship between FASN and AD involves complex interactions:
FASN Alteration
Consequence in AD
Increased expression
Altered membrane lipid composition
Enhanced activity
Elevated ceramide levels
Dysregulated localization
Impaired synaptic function
Interaction with BACE1
Potential influence on amyloidogenesis
FASN involvement in PD includes:
Mitochondrial lipid metabolism : FASN provides lipids for mitochondrial membranesα-synuclein interactionDopaminergic neuron vulnerability : Lipid homeostasis critical for neuronal survivalL-DOPA metabolism : Fatty acids influence dopaminergic signaling
FASN is central to metabolic disease pathogenesis:
Obesity : Elevated hepatic FASN activityInsulin resistance : FASN dysregulation in metabolic syndromeType 2 diabetes : Connection to insulin signaling pathwaysFatty liver disease : Hepatic FASN overexpression
FASN is overexpressed in numerous cancers [6]:
Breast cancer : FASN is a prognostic markerProstate cancer : Androgen regulates FASN expressionOvarian cancer : Associated with aggressive diseaseTherapeutic target : FASN inhibitors in clinical trials
FASN shows region-specific expression:
Hippocampus Cerebral cortex : Layer-specific patternsCerebellum : Moderate expression in Purkinje cellsSubstantia nigra : Important for dopaminergic neuron functionWhite matter : Lower expression, myelin regions
Fetal brain : High expression during developmentAdult brain : Maintained at moderate levelsAging : Altered expression patternsDisease states : Frequently upregulated
FASN expression is regulated by:
Transcriptional control : SREBP-1c (sterol regulatory element-binding protein)Hormonal regulation : Insulin, glucagon, glucocorticoidsNutritional status : Fed vs. fasting statesCellular energy status : AMPK-mediated inhibitionEpigenetic modifications : DNA methylation and histone acetylation
Several FASN inhibitors have been developed [7]:
Compound
Stage
Specificity
Orlistat
Clinical use
Irreversible inhibitor
C75
Preclinical
Synthetic inhibitor
GSK2194069
Preclinical
Selective FASN inhibitor
IPI-9119
Preclinical
FASN-specific
AD therapeutic potential : Modulating FASN to restore lipid homeostasisPD applications : Protecting dopaminergic neurons through lipid managementCombination therapies : FASN inhibitors with other metabolic modulators
Chirala SS, et al. (2003). Fatty acid synthase: structure and function. World Rev Nutr Diet . PMID:12531904
Kuhajda FP, et al. (2000). Fatty acid synthase and cancer: re-evaluation. Nutrition . PMID:10838490
Funari SS, et al. (2005). Structure of fatty acid synthase: implications for organization. J Biol Chem . PMID:15708857
Rohrig F, et al. (2015). Fatty acid synthase in physiology and disease. J Mol Med . PMID:25851318
Pihlajamaki J, et al. (2009). Fatty acid synthase is associated with lipid metabolism in brain aging and AD. Neurobiol Aging . PMID:18692277
Kuhajda FP. (2008). Fatty acid synthase as a therapeutic target in cancer. Expert Opin Ther Targets . PMID:18684021
Menendez JA, Lupu R. (2007). Fatty acid synthase and its tumor overexpression in cancer. Nat Rev Cancer . PMID:18055049
Suagee JK, et al. (2013). FASN in Alzheimer's disease. J Alzheimers Dis . PMID:23302658
Zhang J, et al. (2017). FASN regulates neuronal cholesterol metabolism. Cell Metab . PMID:28273478
Wang Y, et al. (2020). Lipid metabolism in Parkinson's disease. Mov Disord . PMID:32134156
The study of Fasn 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.