CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.

Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid ß oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.

A novel CPT1A covalent inhibitor modulates fatty acid oxidation and CPT1A-VDAC1 axis with therapeutic potential for colorectal cancer.

Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.

Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres.

PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.

The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington's Disease Model by Acting on the Expression of Carnitine-Related Genes.

Huntington's disease (HD) is a dramatic neurodegenerative disorder caused by the abnormal expansion of a CAG triplet in the huntingtin gene, producing an abnormal protein. As it leads to the death of neurons in the cerebral cortex, the patients primarily present with neurological symptoms, but recently metabolic changes resulting from mitochondrial dysfunction have been identified as novel pathological features. The carnitine shuttle is a complex consisting of three enzymes whose function is to transport the long-chain fatty acids into the mitochondria. Here, its pharmacological modification was used to test the hypothesis that shifting metabolism to lipid oxidation exacerbates the HD symptoms. Behavioural and transcriptional analyses were carried out on HD Drosophila model, to evaluate the involvement of the carnitine cycle in this pathogenesis. Pharmacological inhibition of CPT1, the rate-limiting enzyme of the carnitine cycle, ameliorates the HD symptoms in Drosophila, likely acting on the expression of carnitine-related genes.

Molecular Mechanism of Palmitic Acid on Myocardial Contractility in Hypertensive Rats and Its Relationship with Neural Nitric Oxide Synthase Protein in Cardiomyocytes.

OBJECTIVE: It is aimed at investigating the mechanism of palmitic acid (PA) on myocardial contractility in hypertensive rats and its relationship with myocardial neural nitric oxide synthase (nNOS) protein. METHODS: The rats were randomly divided into sham operation group and hypertensive group, with thirty rats in each group, to prepare angiotensin II-induced hypertensive model rats. The blood pressure of rats was measured by the multianimal multichannel tail cuff noninvasive blood pressure system of Kent Coda, USA. The Ionoptix single-cell contraction detection system was used to detect myocardial cells. ATP level of left ventricular cardiomyocytes was determined by luminescence method, and protein was measured by Western blot. RESULTS: Compared with the sham group, systolic blood pressure and diastolic blood pressure were increased in the hypertensive group over 4 weeks; PA increased the contractility of left ventricular cardiomyocytes in normal rats, but not in hypertensive rats, and PA increased the intracellular ATP level of rats in the sham group but not in the hypertension group. In the hypertension group, the expression of nNOS in the cardiomyocytes was significantly increased, and specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) was found to restore the positive inotropic effect of PA in the myocardium of the hypertension group. PA was supplemented after using CPT-1 inhibitor etomoxir (ETO); it was found that ETO inhibited the positive inotropic effect of PA on left ventricular cardiomyocytes in the sham group, and PA was supplemented after using SMTC and ETO, it was found that SMTC + ETO could inhibit the positive inotropic effect of PA on left ventricular cardiomyocytes in myocardium of hypertensive rats. CONCLUSION: PA could increase the contractility of healthy cardiomyocytes, but had no obvious positive effect on the cardiomyocytes of hypertensive rats, PA enhanced the contractility of cardiomyocytes by increasing ATP level in them, and the inhibitory effect of PA on myocardial contractility in hypertensive rats may be related to the increased nNOS and CPT-1 in cardiomyocytes.

Downregulating carnitine palmitoyl transferase 1 affects disease progression in the SOD1 G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS.

E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment.

Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1 -/- and E2f2 -/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1 -/- and E2f2 -/- mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis. SIGNIFICANCE: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2874/F1.large.jpg.

Inhibition of Carnitine Palmitoyltransferase 1A Aggravates Fatty Liver Graft Injury via Promoting Mitochondrial Permeability Transition.

BACKGROUND: Hepatic steatosis is a major risk factor for graft failure due to increased susceptibility of fatty liver to ischemia-reperfusion injury (IRI) during transplantation. Here, we aimed to investigate the role of carnitine palmitoyltransferase 1A (CPT1A) in fatty liver graft injury and to explore the underlying mechanism and therapeutic potential on attenuating hepatic IRI. METHODS: Intragraft CPT1A expression profile and the association with fatty graft injury were investigated in human and rat liver transplantation samples. The underlying mechanism and therapeutic potential of CPT1A activator against IRI were also explored in mouse hepatic ischemia-reperfusion plus major hepatectomy model and in in vitro. RESULTS: CPT1A expression was significantly reduced (P = 0.0019; n = 96) in human fatty liver graft compared with normal one at early phase after transplantation. Low expression of CPT1A was significantly associated with high serum alanine aminotransferase (P = 0.0144) and aspartate aminotransferase (P = 0.0060) levels. The inhibited CPT1A and poor liver function were consistently observed in rat and mouse models with fatty livers. Furthermore, inhibition of CPT1A significantly promoted the translocation of chloride intracellular channel 1 to form chloride ion channel. The dysregulation of chloride ion channel activity subsequently triggered mitochondrial permeability transition (MPT) pore opening, exacerbated cellular oxidative stress, and energy depletion. Importantly, our intravital confocal imaging showed that CPT1A activation attenuated hepatic injury through preventing MPT after reperfusion in fatty mice. CONCLUSIONS: CPT1A inhibition triggered MPT contributed to severe IRI in fatty liver graft. CPT1A restoration may offer therapeutic potential on attenuating hepatic IRI.

Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer.

Resistance to platinum compounds is a major determinant of patient survival in high-grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a data resource composed of dynamic (±carboplatin) protein, post-translational modification, and RNA sequencing (RNA-seq) profiles from intra-patient cell line pairs derived from 3 HGSOC patients before and after acquiring platinum resistance. These profiles reveal extensive responses to carboplatin that differ between sensitive and resistant cells. Higher fatty acid oxidation (FAO) pathway expression is associated with platinum resistance, and both pharmacologic inhibition and CRISPR knockout of carnitine palmitoyltransferase 1A (CPT1A), which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. The results are further validated in patient-derived xenograft models, indicating that CPT1A is a candidate therapeutic target to overcome platinum resistance. All multiomic data can be queried via an intuitive gene-query user interface (https://sites.google.com/view/ptrc-cell-line).

Inhibition of carnitine palmitoyl transferase 1A-induced fatty acid oxidation suppresses cell progression in gastric cancer.

BACKGROUND: Gastric cancer (GC) has a high rate of metastasis which thereason leading to death. Carnitine palmitoyl transferase 1a (CPT1A) has been reported to play a critical obstacle to various types of cancer progression, which is an attractive focus in anti-cancer therapy. However, the underlying molecular mechanisms of CPT1A involved in GC have not been clarified clear. METHODS: To determine the expression of CPT1A in human GC tissues and cells and illustrate whether it is correlated with the clinical pathologic characteristics and prognosis in GC patients. Its roles and potential mechanisms in regulating tumor growth and invasion were evaluated by CPT1A knockdown/overexpression of GC cells in vitro. RESULTS: Marked upregulation of CPT1A protein expression was observed in GC cells and tissues, which was associated with grade, pathological stage, lymph node metastasis and poor prognosis in patients with GC. CPT1A overexpression also promoted the proliferation, invasion, EMT process of GC cells. In addition, CPT1A upregulation activated GC cell fatty acid oxidation (FAO) via increasing NADP+/NADPH ratio, whereas inhibiting of FAO abolished the effects of CPT1A on GC cell proliferation and migration. CONCLUSION: Our results examine that CPT1A-mediated FAO activation increases GC cell proliferation and migration, supporting that CPT1A is a useful prognostic biomarker and an attractive focus for GC.

Effects and mechanisms of fatty acid metabolism­mediated glycolysis regulated by betulinic acid­loaded nanoliposomes in colorectal cancer.

Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA­loaded nanoliposomes (BA­NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA­NLs in fatty acid metabolism­mediated glycolysis, and investigate the role of key targets, such as acyl­CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase­1 (PFK­1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA­NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti­CRC function of BA­NLs. Moreover, the effects of BA­NLs were further validated by demonstrating that the key targets of HK2, PFK­1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA­NLs, which play key roles in the inhibition of glycolysis and fatty acid­mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.

Inhibition of CPT2 exacerbates cardiac dysfunction and inflammation in experimental endotoxaemia.

The suppression of energy metabolism is one of cornerstones of cardiac dysfunction in sepsis/endotoxaemia. To investigate the role of fatty acid oxidation (FAO) in the progression of inflammation-induced cardiac dysfunction, we compared the effects of FAO-targeting compounds on mitochondrial and cardiac function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia. In LPS-treated mice, endotoxaemia-induced inflammation significantly decreased cardiac FAO and increased pyruvate metabolism, while cardiac mechanical function was decreased. AMP-activated protein kinase activation by A769662 improved mitochondrial FAO without affecting cardiac function and inflammation-related gene expression during endotoxaemia. Fatty acid synthase inhibition by C75 restored both cardiac and mitochondrial FAO; however, no effects on inflammation-related gene expression and cardiac function were observed. In addition, the inhibition of carnitine palmitoyltransferase 2 (CPT2)-dependent FAO by aminocarnitine resulted in the accumulation of FAO intermediates, long-chain acylcarnitines, in the heart. As a result, cardiac pyruvate metabolism was inhibited, which further exacerbated inflammation-induced cardiac dysfunction. In conclusion, although inhibition of CPT2-dependent FAO is detrimental to cardiac function during endotoxaemia, present findings show that the restoration of cardiac FAO alone is not sufficient to recover cardiac function. Rescue of cardiac FAO should be combined with anti-inflammatory therapy to ameliorate cardiac dysfunction in endotoxaemia.

Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models.

The etiology of CNS diseases including multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.

Tartronic acid promotes de novo lipogenesis and inhibits CPT-1ß by upregulating acetyl-CoA and malonyl-CoA.

As a dicarboxylic acid with the structural formula HOOCCH (OH) COOH, tartronic acid is considered as an inhibitor of the transformation of carbohydrates into fat under fat-deficient diet conditions. However, the effect of tartronic acid on lipogenesis under high-fat diet conditions has yet to be established. In this work, we investigated the regulatory role of tartronic acid in lipogenesis in 3T3-L1 adipocytes and C57BL/6J mice. The results confirmed that tartronic acid promoted weight gain (without affecting food intake) and induced adipocyte hypertrophy in epididymal white adipose tissue and lipid accumulation in the livers of high-fat diet-induced obese mice. In vitro, tartronic acid promoted 3T3-L1 adipocyte differentiation by increasing the protein expression of FABP-4, PPARγ and SREBP-1. Moreover, the contents of both acetyl-CoA and malonyl-CoA were significantly upregulated by treatment with tartronic acid, while the protein expression of CPT-1ß were inhibited. In summary, we proved that tartronic acid promotes lipogenesis by serving as substrates for fatty acid synthesis and inhibiting CPT-1ß, providing a new perspective for the study of tartronic acid.

Arctigenin disrupts NLRP3 inflammasome assembly in colonic macrophages via downregulating fatty acid oxidation to prevent colitis-associated cancer.

Arctigenin, the major active constituent of Fructus Arctii, has been reported to inhibit the growth of various tumors and alleviate colitis. This study aimed to prove the protective effect of arctigenin on colitis-associated cancer (CAC) and explore its mechanisms. Orally administered arctigenin prevented the progression of colitis and protected against colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC mice. Arctigenin downregulated NLRP3 inflammasome activation and fatty acid oxidation (FAO) metabolism in macrophages, as determined by untargeted metabolomics. Arctigenin also inhibited the expression of carnitine palmitoyltransferase 1 (CPT1), reduced the acetylation of α-tubulin, and disrupted NLRP3 complex formation, which in turn inactivated the NLRP3 inflammasome. Downregulation of the CPT1-FAO-acetyl-coenzyme A (acetyl-CoA)-acetylated α-tubulin pathway was observed to inhibit the effect of arctigenin on NLRP3 inflammasome assembly, as confirmed by CPT1 overexpression. Lastly, arctigenin was shown to inhibit NLRP3 inflammasome activation and improve CAC in mice, and the effect was significantly diminished by the overexpression of adeno-associated virus (AAV)9-CPT1. Taken together, these results show that the inhibition of NLRP3 inflammasome assembly in macrophages due to FAO downregulation contributes to the preventative effect of arctigenin against CAC. Our findings highlight the potential value of arctigenin to reduce the risk of CAC in patients with colitis.

Targeting CPT1B as a potential therapeutic strategy in castration-resistant and enzalutamide-resistant prostate cancer.

BACKGROUND: Prostate cancer is characterized by aberrant lipid metabolism, including elevated fatty acid oxidation. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of fatty acid oxidation. This study aimed to determine if CPT1B has a critical role in prostate cancer progression and to identify its regulatory mechanism. METHODS: CPT1B expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases was compared with patient survival data. A tissue microarray was constructed with 60 samples of prostate cancer and immunohistochemically stained for CPT1B. Castration-resistant prostate cancer (CRPC) cell lines 22RV1 and C4-2 in which CPT1B expression had been stably knocked down were established; and cell proliferation, cell cycle distribution, and invasion were investigated by Cell Counting Kit-8 (CCK-8) and colony formation assays, flow cytometry, and Transwell assays, respectively. To examine the impact of androgen receptor (AR) inhibition on CPT1B expression, JASPAR CORE was searched to identify AR-binding sites in CPT1B. Dual luciferase and ChIP assays were performed to confirm CPT1B activity and AR binding, respectively. Differentially expressed genes (DEGs) in prostate cancer underwent gene set enrichment analysis (GSEA). Enzalutamide-resistant C4-2 cells were generated and the mechanism of enzalutamide resistance and downstream signaling pathway changes of CPT1B to C4-2 was explored through CCK-8 test. RESULTS: CPT1B expression was upregulated in human prostate cancer compared with normal prostate tissue and was associated with poor disease-free survival and overall survival. Silencing of CPT1B resulted in downregulated cell proliferation, reduced S-phase distribution, and lower invasive ability, whereas the opposite was observed in CRPC cells overexpressing CPTB1. DEGS in prostate cancer were correlated with G-protein-coupled receptor signaling, molecular transducer activity, and calcium ion binding. AR may regulate CPT1B expression and activity via specific binding sites, as confirmed by dual luciferase and ChIP assays. The CCK-8 experiment demonstrated that CPT1B overexpression in C4-2 cells did not significantly increase the ability of enzalutamide resistance. However, overexpression of CPT1B in C4-2R cells significantly increased the enzalutamide resistance. Upregulation of CPT1B expression increased AKT expression and phosphorylation. CONCLUSIONS: CPT1B is upregulated in prostate cancer and is correlated with poor prognosis, indicating its potential as a biomarker. AR inhibits the transcription of CPT1B. In the CRPC cell line, overexpression of CPT1B alone cannot promote enzalutamide resistance, but in the drug-resistant line C4-2R, overexpression of CPT1B can promote the resistance of C4-2R to enzalutamide.

Pharmacological inhibition of carnitine palmitoyl transferase 1 inhibits and reverses experimental autoimmune encephalitis in rodents.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-ß (IFN-ß), IFN-ß had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-ß and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment.

Lipid in Renal Carcinoma: Queen Bee to Target?

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer subtype, characterized by a lipid storage phenotype. We found that carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of mitochondrial fatty acid (FA) transport, is repressed by hypoxia-inducible factors (HIFs), reducing FA oxidation (FAO). Altering lipid metabolism may be a new therapeutic avenue in ccRCC.

CPT1A-mediated Fat Oxidation, Mechanisms, and Therapeutic Potential.

Energy homeostasis during fasting or prolonged exercise depends on mitochondrial fatty acid oxidation (FAO). This pathway is crucial in many tissues with high energy demand and its disruption results in inborn FAO deficiencies. More than 15 FAO genetic defects have been currently described, and pathological variants described in circumpolar populations provide insights into its critical role in metabolism. The use of fatty acids as energy requires more than 2 dozen enzymes and transport proteins, which are involved in the activation and transport of fatty acids into the mitochondria. As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria. The regulation of CPT1A is complex and has several layers that involve genetic, epigenetic, physiological, and nutritional modulators. It is ubiquitously expressed in the body and associated with dire consequences linked with genetic mutations, metabolic disorders, and cancers. This makes CPT1A an attractive target for therapeutic interventions. This review discusses our current understanding of CPT1A expression, its role in heath and disease, and the potential for therapeutic opportunities targeting this enzyme.

Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers.

Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers.