CEPT1

CEPT1 is a dual-specificity, ER-resident enzyme that catalyzes the final committed step of the Kennedy pathway, transferring a phosphobase from CDP-choline or CDP-ethanolamine to diacylglycerol to generate phosphatidylcholine (PC) and phosphatidylethanolamine (PE) (PMID:12216837). It prefers unsaturated DAG acceptors and is subject to product activation, and it accounts for the majority of cellular choline-phospholipid biosynthesis (PMID:12216837, PMID:34331935). Its ER localization is functionally distinct from the Golgi-resident related transferases EPT1 and CHPT1, which favor alkyl-acyl and plasmalogen/PUFA substrates, and only ER-synthesized PC made by CEPT1 feedback-regulates CCTα — loss of CEPT1 drives posttranscriptional CCTα upregulation, dephosphorylation, and constitutive nuclear-membrane localization together with aberrant lipid droplet accumulation, all reversible by PC repletion (PMID:32576654, PMID:34331935, PMID:36871755). Beyond bulk phospholipid supply, CEPT1 is essential for endothelial proliferation, migration, and angiogenesis in vivo, acting upstream of a PPARα→VEGF-A→VEGFR2→Akt/eNOS signaling axis (PMID:33214136, PMID:41263082). CEPT1 also interacts with and stabilizes LPCAT3 and thereby suppresses ferroptosis (PMID:38430542). No high-confidence structural model of the enzyme has been characterized in the available corpus.

1. 2002 High

   Established CEPT1 as a single dual-specificity enzyme producing both PC and PE, defining its core catalytic identity and substrate preferences.

   Evidence Mixed-micellar in vitro enzyme assay in a heterologous system lacking endogenous activity, with Km determination and inhibitor profiling

   PMID:12216837

   Open questions at the time

   • No structural basis for dual specificity or the inferred lipid activation sites
   • In vitro kinetics do not establish in-cell flux contribution
2. 2020 High

   Resolved the division of labor among phosphobase transferases by showing CEPT1 is ER-localized and drives PE synthesis from shorter-chain species, distinct from Golgi-resident EPT1.

   Evidence Immunohistochemistry, CRISPR knockout cells, metabolic labeling, in vitro assay, and LC-MS lipidomics in HEK293

   PMID:32576654

   Open questions at the time

   • Does not address regulation of CEPT1 substrate channeling
   • Localization determinants not mapped
3. 2021 High

   Quantified CEPT1 as the dominant contributor to choline phospholipid biosynthesis relative to Golgi-resident CHPT1/CPT1.

   Evidence CRISPR KO/rescue HEK293 cells, radiolabeled choline labeling, qPCR, and deuterium-labeled LC-MS/MS

   PMID:34331935

   Open questions at the time

   • Tissue-specific relative contributions not established
   • Does not address downstream signaling consequences
4. 2023 High

   Demonstrated that only ER-synthesized PC made by CEPT1 feedback-regulates CCTα activation state and lipid droplet biogenesis, linking the enzyme to lipid homeostatic control.

   Evidence CRISPR KO in U2OS, [14C]-choline labeling, CCTα localization imaging, PC liposome rescue, and LD quantification

   PMID:36871755

   Open questions at the time

   • Molecular mechanism of how ER-PC pool is sensed by CCTα not resolved
   • Nuclear LD function not defined
5. 2020 High

   Placed CEPT1 upstream of PPARα in endothelial angiogenic signaling through genetic epistasis, extending its role from lipid metabolism to vascular function.

   Evidence Conditional EC-specific Cept1 knockout, hindlimb ischemia model, Cept1/Ppara double KO, siRNA knockdown, and fenofibrate rescue

   PMID:33214136

   Open questions at the time

   • How PC/PE metabolism mechanistically activates PPARα not established
   • Exogenous PC failed to rescue, leaving the lipid signal undefined
6. 2024 Medium

   Identified a phospholipid-synthesis-independent role: CEPT1 binds and stabilizes LPCAT3 and suppresses ferroptosis.

   Evidence Proteomic interaction screen, co-immunoprecipitation, and ferroptosis assays with CEPT1 modulation

   PMID:38430542

   Open questions at the time

   • Phospholipase interactions and PUFA-phospholipid degradation mechanism not biochemically resolved
   • Direct vs indirect contribution to ferroptosis not separated from synthesis function
7. 2025 Medium

   Gain-of-function established CEPT1 as a positive driver of a PPARα→VEGF-A→VEGFR2→Akt/eNOS angiogenic cascade.

   Evidence EC-specific Cept1 overexpression mouse, scRNA-seq, inhibitor pathway dissection, and sprouting/ischemia assays

   PMID:41263082

   Open questions at the time

   • Single-lab gain-of-function correlation; direct molecular link from CEPT1 to PPARα still missing
   • Inhibitor epistasis does not prove a linear pathway
8. 2026 Medium

   Connected CEPT1 deficiency to phospholipid imbalance that triggers ER stress and mitochondrial Ca2+/oxidative stress, and identified FOXA1 as a direct transcriptional activator in airway epithelium.

   Evidence FOXA1 transcriptional studies, CEPT1 KD/OE in airway epithelial cells, ER stress and Ca2+/ROS assays, asthma mouse model with rescue

   PMID:42176270

   Open questions at the time

   • Causal chain from phospholipid imbalance to ER stress not dissected step-by-step
   • Tissue specificity of FOXA1 regulation not generalized
9. 2026 Low

   Linked CEPT1 to nucleotide-driven metabolic reprogramming, with CTPS1-supplied CTP boosting CEPT1 expression to support mitochondrial homeostasis and BNIP3 mitophagy in lymphoma cells.

   Evidence scRNA-seq, CTPS1 KD/OE in DLBCL cells, CEPT1 expression measurement, and mitophagy/BNIP3 assays

   PMID:41865720

   Open questions at the time

   • Primarily scRNA-seq and knockdown with limited biochemical validation
   • Direct effect of CEPT1 lipids on mitophagy not reconstituted

• How CEPT1-derived phospholipid pools are mechanistically transduced into PPARα activation and the structural basis of its dual catalytic specificity remain unresolved.
• No structural model of the enzyme
• Identity of the lipid signal coupling CEPT1 to PPARα unknown
• Phospholipase partners in ferroptosis suppression unconfirmed