Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

Carrasco, P.; Sahún, Ignasi; McDonald, Jerome J.; Ramírez, Sara; Jacas, Jordi; Gratacós, Esther; Sierra, Adriana Y.; Serra, Dolors; Herrero, Laura; Acker‐Palmer, Amparo; Hegardt, Fausto G.; Dierssen, Mara; Casals, Núria

doi:10.1074/jbc.m111.337493

Cited by 69 publications

(103 citation statements)

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“…9,22 CPT1C has been recently demonstrated to be expressed in pyramidal neurons of hippocampus and is located in the ER. Sierra et al 14 demonstrated that CPT1C possessed CPT activity, while Carrasco et al 23 indicated that CPT1C may regulate ceramide levels in neurons. Nevertheless, it has been reported that CPT1C conserves the affinity for Malonyl-CoA, which inhibits all the CPT1 family members.…”

Section: Discussionmentioning

confidence: 99%

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

et al. 2013

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Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors. Hypoxia is an important chronic stress on tumor cell growth and has been shown to correlate with poor disease-free and reduced overall survival in a variety of carcinomas and sarcomas. 1 To enhance survival in an altered environment such as hypoxia cancer cells undergo a so-called metabolic transformation. [2][3][4] The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells upregulate glycolysis to limit their energy consumption. However, there is increasing evidence that not only glucose metabolism, but also fatty acid oxidation (FAO) is involved in metabolic transformation. Although glucose seems to be the major energy source for tumor growth and survival, there is increasing evidence that alternative energy sources such as fatty acid metabolism are altered in cancer cells, even under hypoxic conditions. Indeed, fatty acid synthase has been found to be upregulated in many human cancers, 5 and inhibitors of the fatty acid synthase show antitumor activity. 6 As recently published, we identified carnitine palmitoyltransferase (CPT) 1C (CPT1C) as a potential novel p53-target gene. 7 By their restriction of fatty acid import into mitochondria, 4 the CPT 1 (CPT1) family of enzymes represent key regulatory factors of FAO. There are three tissue-specific isoforms of CPT1: CPT1A that is found in liver, CPT1B in muscle and CPT1C in brain and testes. Loss-of-function of CPT1C was generated in mouse embryonic stem cells (Cpt1c gt/gt ES cells). Importantly, Cpt1c gt/gt ES cells readily succumbed to cell death under hypoxic conditions, whereas control cells were resistant. ES cells deficient for CPT1C showed a spontaneous induction in...

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Section: Discussionmentioning

confidence: 99%

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

et al. 2013

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“…When ceramide levels were analyzed in various regions of the brain (hippocampus, motor cortex, cerebellum, and striatum), the content of the most abundant ceramide in brain (C18:0), and its derivative sphingosine was lowered in fasted CPT1C KO mice [30,47]. Moreover, overexpression of CPT1C in the arcuate (Arc) nucleus increased ceramide levels in this nucleus, while CPT1C KO mice did not show the expected increase in ceramide in response to fasting or to ghrelin treatment.…”

Section: Metabolism Of Ceramidesmentioning

confidence: 99%

“…To confirm that CPT1C-induced ceramide modulation occurs in neurons and not in other brain cells, an in vitro model of pure neurons was used in following experiments [47]. CPT1C overexpression in cultured hippocampal neurons increased ceramide almost two-fold, while cultured neurons from CPT1C KO mice showed a notable reduction.…”

Section: Metabolism Of Ceramidesmentioning

confidence: 99%

“…In situ hybridization on mouse coronal brain sections showed high expression of this protein in the hippocampus [1], thereby suggesting that it is likely to play a role in this brain region. Therefore, the repercussion of the CPT1C KO genotype on memory consolidation and learning processes was evaluated [47]. In the hippocampal-dependent…”

Section: Cognitionmentioning

confidence: 99%

“…This poorer performance was not associated with motor deficits because swimming speed remained unaltered in 3-month old animals. Platform removal (to test visuospatial memory) and platform relocation (to test cognitive flexibility) revealed that CPT1C KO deficits were limited to the learning phase [47].…”

Section: Cognitionmentioning

confidence: 99%

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Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

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110

101

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Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

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Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

et al. 2015

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The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.OBJECTIVE To identify the genetic cause for a novel form of pure autosomal dominant HSP. DESIGN, SETTING, AND PARTICIPANTS We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. MAIN OUTCOME AND MEASUREMutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTSWe identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c −/− mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.CONCLUSIONS AND RELEVANCE This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.

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Ceramide Levels Regulated by Carnitine Palmitoyltransferase 1C Control Dendritic Spine Maturation and Cognition

Cited by 69 publications

References 26 publications

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

Carnitine palmitoyltransferase 1C: From cognition to cancer

Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

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