CERS6 Gene

CERS6 — Ceramide Synthase 6

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CERS6 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CERS6</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ceramide Synthase 6</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2q33.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[253782](https://www.ncbi.nlm.nih.gov/gene/253782)</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>[615990](https://omim.org/entry/615990)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>[ENSG00000166922](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166922)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q3YGD3](https://www.uniprot.org/uniprot/Q3YGD3)</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Ceramide synthase (Lag1 family)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's disease, Parkinson's disease, metabolic syndrome, skin barrier disorders</td>
</tr>
</table>

Introduction

CERS6 — Ceramide Synthase 6

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CERS6 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CERS6</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ceramide Synthase 6</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2q33.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[253782](https://www.ncbi.nlm.nih.gov/gene/253782)</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>[615990](https://omim.org/entry/615990)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>[ENSG00000166922](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166922)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q3YGD3](https://www.uniprot.org/uniprot/Q3YGD3)</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Ceramide synthase (Lag1 family)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's disease, Parkinson's disease, metabolic syndrome, skin barrier disorders</td>
</tr>
</table>

Introduction

The CERS6 gene (Ceramide Synthase 6) encodes a member of the ceramide synthase family that catalyzes the N-acylation of sphingoid bases to produce ceramides. CERS6 exhibits substrate specificity for C14- and C16-dihydroceramides, making it the primary enzyme responsible for generating the most abundant ceramide species in mammalian cells. Ceramides serve as critical structural components of cellular membranes, especially in lipid rafts, and function as second messengers in numerous signaling pathways that regulate cell fate, metabolism, and inflammation.

In the brain, CERS6 plays a pivotal role in maintaining lipid homeostasis essential for neuronal function. Alterations in CERS6 expression and activity have been implicated in the pathogenesis of Alzheimer's disease, where ceramide metabolism is profoundly disrupted. The accumulation of specific ceramide species, particularly C16-ceramide, contributes to amyloidogenic APP processing, synaptic dysfunction, and neuronal death. Beyond neurodegeneration, CERS6 is involved in metabolic disorders, cancer biology, and skin barrier function.

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Gene Structure and Protein

The human CERS6 gene is located on chromosome 2q33.3 and encodes a 384-amino acid transmembrane protein localized to the endoplasmic reticulum. Like other ceramide synthases (CerS1-6), CERS6 contains the Lag1 motif (LAG1 consensus) required for ceramide synthase activity.

Catalytic properties:

• Substrate specificity: CERS6 preferentially utilizes C14- and C16-fatty acyl-CoA substrates (myristoyl-CoA and palmitoyl-CoA)
• Product profile: Generates C14- and C16-ceramides (ceramides with 14- and 16-carbon acyl chains)
• Localization: Endoplasmic reticulum membrane, where de novo ceramide synthesis occurs
• Regulation: Transcriptionally regulated by SREBP, PPARs, and cellular stress responses

Cellular Functions

Ceramide Biosynthesis

CERS6 is a central enzyme in the de novo ceramide biosynthesis pathway:

Lipid Metabolism and Energy Homeostasis

CERS6 integrates lipid metabolism with systemic energy balance:

• Lipid droplet regulation: Ceramide accumulation promotes lipid droplet formation
• Insulin signaling: CERS6 activity modulates insulin sensitivity through ceramide-mediated inhibition of Akt
• β-oxidation: Ceramides can be catabolized to sphingosine and then to palmityl-CoA for mitochondrial oxidation
• Adipocyte function: CERS6 in adipocytes regulates lipogenesis and adipokine secretion

Membrane Composition and Lipid Rafts

CERS6-generated ceramides are enriched in lipid rafts:

• Lipid raft formation: Ceramide promotes raft coalescence and stability
• Membrane protein partitioning: raft-localized proteins include APP, BACE1, and various receptors
• Signal transduction: Raft composition affects receptor signaling kinetics and amplitude
• Synaptic membrane maintenance: Neuronal rafts are essential for synaptic function

Expression Pattern

CERS6 exhibits tissue-specific expression:

• Brain: High expression in cortex, hippocampus, and cerebellum; expressed in neurons and astrocytes
• Liver: Strong expression; primary site of systemic ceramide metabolism
• Adipose tissue: Moderate expression; regulates lipid storage and systemic metabolism
• Skin: Highest expression in epidermis; essential for stratum corneum formation
• Pancreas: Expressed in β-cells; regulates insulin secretion

• Cerebral cortex (layer V pyramidal neurons)
• Hippocampus (CA1 and dentate gyrus)
• Cerebellar Purkinje cells
• Substantia nigra dopaminergic neurons

Disease Associations

Alzheimer's Disease

CERS6 is strongly implicated in AD pathogenesis:

• Amyloid processing: C16-ceramide generated by CERS6 promotes amyloidogenic APP processing by enhancing β-secretase (BACE1) activity. Lipid rafts enriched in CERS6-derived ceramides concentrate APP and BACE1 in proximity [@cers6_alzheimer]
• Tau pathology: Ceramide accumulation accelerates tau phosphorylation through activation of protein phosphatases and kinases
• Synaptic dysfunction: Ceramide disrupts synaptic membrane integrity and impairs neurotransmitter release
• Neuronal death: C16-ceramide triggers apoptosis through mitochondrial pathways and JNK activation
• Lipid raft alterations: AD brain shows increased C16-ceramide in lipid rafts, disrupting normal raft function and promoting amyloidogenesis

Parkinson's Disease

Emerging evidence links CERS6 to PD:

• Dopaminergic neuron vulnerability: CERS6 is highly expressed in substantianigra neurons, which are selectively vulnerable in PD
• Alpha-synuclein aggregation: Ceramide promotes alpha-synuclein aggregation and oligomerization
• Mitochondrial dysfunction: Ceramide accumulation impairs mitochondrial complex activity
• ER stress: CERS6 dysregulation contributes to ER stress in PD models

Metabolic Syndrome

CERS6 links lipid metabolism to systemic disease:

• Insulin resistance: Ceramide accumulation in liver and skeletal muscle impairs insulin signaling
• Obesity: CERS6 expression is upregulated in obesity and promotes adipogenesis
• Type 2 diabetes: Ceramide-mediated β-cell dysfunction contributes to diabetes pathogenesis
• Cardiovascular disease: Circulating ceramides are associated with atherosclerosis and cardiovascular events

Cancer

CERS6 exhibits context-dependent effects in cancer:

• Tumor suppression: CERS6-derived C16-ceramide promotes apoptosis in many cancer types
• Tumor progression: Some cancers upregulate CERS6 to generate pro-survival ceramides
• Chemotherapy response: CERS6 mediates the anticancer effects of various chemotherapeutic agents

Therapeutic Implications

Targeting CERS6 offers therapeutic opportunities:

Key Publications

See Also

• [Ceramide metabolism in neurodegeneration](/mechanisms/ceramide-signaling-neurodegeneration)
• [Lipid rafts in Alzheimer's disease](/mechanisms/lipid-rafts-alzheimers)
• [Sphingolipid metabolism](/mechanisms/sphingolipid-metabolism)
• [Alzheimer's disease](/diseases/alzheimers-disease)
• [Parkinson's disease](/diseases/parkinsons-disease)
• [BACE1](/proteins/bace1-protease)
• [APP](/proteins/amyloid-precursor-protein)
• [Lipid metabolism in neurodegeneration](/mechanisms/lipid-metabolism-neurodegeneration)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving CERS6 Gene discovered through SciDEX knowledge graph analysis: