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1.
Cancer Lett ; 595: 217006, 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-38823763

RESUMO

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.


Assuntos
Carcinoma Hepatocelular , Carnitina O-Palmitoiltransferase , Neoplasias Hepáticas , Mutação , Proteína Supressora de Tumor p53 , Humanos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Metabolismo dos Lipídeos/genética , Transdução de Sinais , Acetilcoenzima A/metabolismo , Regulação Neoplásica da Expressão Gênica , Masculino
2.
PLoS One ; 19(6): e0305571, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38885281

RESUMO

Congenital heart disease (CHD) is the most serious form of heart disease, and chronic hypoxia is the basic physiological process underlying CHD. Some patients with CHD do not undergo surgery, and thus, they remain susceptible to chronic hypoxia, suggesting that some protective mechanism might exist in CHD patients. However, the mechanism underlying myocardial adaptation to chronic hypoxia remains unclear. Proteomics was used to identify the differentially expressed proteins in cardiomyocytes cultured under hypoxia for different durations. Western blotting assays were used to verify protein expression. A Real-Time Cell Analyzer (RTCA) was used to analyze cell growth. In this study, 3881 proteins were identified by proteomics. Subsequent bioinformatics analysis revealed that proteins were enriched in regulating oxidoreductase activity. Functional similarity cluster analyses showed that chronic hypoxia resulted in proteins enrichment in the mitochondrial metabolic pathway. Further KEGG analyses found that the proteins involved in fatty acid metabolism, the TCA cycle and oxidative phosphorylation were markedly upregulated. Moreover, knockdown of CPT1A or ECI1, which is critical for fatty acid degradation, suppressed the growth of cardiomyocytes under chronic hypoxia. The results of our study revealed that chronic hypoxia activates fatty acid metabolism to maintain the growth of cardiomyocytes.


Assuntos
Ácidos Graxos , Miócitos Cardíacos , Proteômica , Proteômica/métodos , Miócitos Cardíacos/metabolismo , Ácidos Graxos/metabolismo , Animais , Hipóxia Celular , Adaptação Fisiológica , Ratos , Miocárdio/metabolismo , Miocárdio/patologia , Hipóxia/metabolismo , Proliferação de Células , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética
3.
Chem Biol Interact ; 398: 111107, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38866309

RESUMO

Benzene is the main environmental pollutant and risk factor of childhood leukemia and chronic benzene poisoning. Benzene exposure leads to hematopoietic stem and progenitor cell (HSPC) dysfunction and abnormal blood cell counts. However, the key regulatory targets and mechanisms of benzene hematotoxicity are unclear. In this study, we constructed a benzene-induced hematopoietic damage mouse model to explore the underlying mechanisms. We identified that Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was significantly reduced in benzene-exposed mice. Moreover, targeting IGF2BP1 effectively mitigated damages to hematopoietic function and hematopoietic molecule expression caused by benzene in mice. On the mechanics, by metabolomics and transcriptomics, we discovered that branched-chain amino acid (BCAA) metabolism and fatty acid oxidation were key metabolic pathways, and Branched-chain amino acid transaminase 1 (BCAT1) and Carnitine palmitoyltransferase 1a (CPT1A) were critical metabolic enzymes involved in IGF2BP1-mediated hematopoietic injury process. The expression of the above molecules in the benzene exposure population was also examined and consistent with animal experiments. In conclusion, targeting IGF2BP1 alleviated hematopoietic injury caused by benzene exposure, possibly due to the reprogramming of BCAA metabolism and fatty acid oxidation via BCAT1 and CPT1A metabolic enzymes. IGF2BP1 is a potential regulatory and therapeutic target for benzene hematotoxicity.


Assuntos
Aminoácidos de Cadeia Ramificada , Benzeno , Ácidos Graxos , Oxirredução , Animais , Benzeno/toxicidade , Aminoácidos de Cadeia Ramificada/metabolismo , Ácidos Graxos/metabolismo , Oxirredução/efeitos dos fármacos , Camundongos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos
4.
Anal Chem ; 96(26): 10851-10859, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38912707

RESUMO

Mitochondrial Membrane Chromatography (MMC) is a bioaffinity chromatography technique developed to study the interaction between target proteins embedded in the mitochondrial membrane and their ligand compounds. However, the MMC stationary phases (MMSP) prepared by chemical immobilization are prone to nonspecific binding in candidate agent screening inevitably. To address these challenges, Twin Strep-Tag/Strep Tactin was employed to establish a specific affinity system in the present study. We prepared a carnitine palmitoyltransferase 1A (CPT1A) MMSP by specifically linking Strep-tactin-modified silica gel with the Twin Strep-Tag on the CPT1A-oriented mitochondrial membrane. This Twin Strep-Tag/Strep Tactin modified CPT1A/MMC method exhibited remarkably better retention behavior, longer stationary phase lifespan, and higher screening specificity compared with previous MMC systems with glutaraldehyde immobilization. We adopted the CPT1A-specific MMC system in screening CPT1A ligands from traditional Chinese medicines, and successfully identified novel candidate ligands: ononin, isoliquiritigenin, and aloe-emodin, from Glycyrrhiza uralensis Fisch and Senna tora (L.) Roxb extracts. Biological assessments illustrated that the compounds screened promote CPT1A enzyme activity without affecting CPT1A protein expression, as well as effectively reduce the lipid droplets and triglyceride levels in the high fat induction HepG2 cells. The results suggest that we have developed an MMC system, which is promising for studying the bioaffinity of mitochondrial membrane proteins to candidate compounds. This system provides a platform for a key step in mitochondrial medicine discovery, especially for bioactive molecule screening from complex herbal extracts.


Assuntos
Carnitina O-Palmitoiltransferase , Metabolismo dos Lipídeos , Membranas Mitocondriais , Humanos , Carnitina O-Palmitoiltransferase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Cromatografia de Afinidade , Ligantes
5.
Nat Metab ; 6(6): 1092-1107, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38773347

RESUMO

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.


Assuntos
Proliferação de Células , Glicólise , Gotículas Lipídicas , Lipólise , Mitocôndrias , Oxirredução , Gotículas Lipídicas/metabolismo , Animais , Mitocôndrias/metabolismo , Camundongos , Humanos , Masculino , Metabolismo dos Lipídeos , Perilipina-2/metabolismo , Fosforilação , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral
6.
Acta Physiol (Oxf) ; 240(7): e14159, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38767438

RESUMO

AIM: Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN. METHODS: The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR. RESULTS: ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN. CONCLUSION: Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.


Assuntos
Carnitina O-Palmitoiltransferase , Nefropatias Diabéticas , Ferroptose , Metabolismo dos Lipídeos , Ativação de Macrófagos , Animais , Humanos , Masculino , Camundongos , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Ferroptose/fisiologia , Metabolismo dos Lipídeos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredutases atuantes sobre Doadores de Grupo Enxofre
7.
Redox Biol ; 73: 103184, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38718533

RESUMO

RATIONALE: The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, the precise roles of Sirt5 in cardiac lipotoxicity and DbCM remain unknown. OBJECTIVE: This study aims to elucidate the role and underlying mechanism of Sirt5 in the context of cardiac lipotoxicity and DbCM. METHODS AND RESULTS: The expression of myocardial Sirt5 was found to be modestly elevated in diabetic heart failure patients and mice. Cardiac dysfunction, hypertrophy and lipotoxicity were exacerbated by ablation of Sirt5 but improved by forced expression of Sirt5 in diabetic mice. Notably, Sirt5 deficiency impaired FAO without affecting the capacity of FA uptake in the diabetic heart, leading to accumulation of FA intermediate metabolites, which mainly included medium- and long-chain fatty acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), a crucial enzyme involved in the reconversion of fatty acyl-carnitines to fatty acyl-CoA and facilitating FAO, as the functional succinylated substrate mediator of Sirt5. Succinylation of Lys424 in CPT2 was significantly increased by Sirt5 deficiency, leading to the inactivation of its enzymatic activity and the subsequent accumulation of fatty acyl-carnitines. CPT2 K424R mutation, which mitigated succinylation modification, counteracted the reduction of enzymatic activity in CPT2 mediated by Sirt5 deficiency, thereby attenuating Sirt5 knockout-induced FAO impairment and lipid deposition. CONCLUSIONS: Sirt5 deficiency impairs FAO, leading to cardiac lipotoxicity in the diabetic heart through the succinylation of Lys424 in CPT2. This underscores the potential roles of Sirt5 and CPT2 as therapeutic targets for addressing DbCM.


Assuntos
Carnitina O-Palmitoiltransferase , Cardiomiopatias Diabéticas , Ácidos Graxos , Metabolismo dos Lipídeos , Miócitos Cardíacos , Sirtuínas , Animais , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Sirtuínas/metabolismo , Sirtuínas/genética , Camundongos , Ácidos Graxos/metabolismo , Miócitos Cardíacos/metabolismo , Humanos , Masculino , Oxirredução , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações
8.
Oncoimmunology ; 13(1): 2352179, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38746869

RESUMO

Cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic heterogeneity, with specific subsets implicated in immunosuppression in various malignancies. However, whether and how they attenuate anti-tumor immunity in gastric cancer (GC) remains elusive. CPT1C, a unique isoform of carnitine palmitoyltransferase pivotal in regulating fatty acid oxidation, is briefly indicated as a protumoral metabolic mediator in the tumor microenvironment (TME) of GC. In the present study, we initially identified specific subsets of fibroblasts exclusively overexpressing CPT1C, hereby termed them as CPT1C+CAFs. Subsequent findings indicated that CPT1C+CAFs fostered a stroma-enriched and immunosuppressive TME as they correlated with extracellular matrix-related molecular features and enrichment of both immunosuppressive subsets, especially M2-like macrophages, and multiple immune-related pathways. Next, we identified that CPT1C+CAFs promoted the M2-like phenotype of macrophage in vitro. Bioinformatic analyses unveiled the robust IL-6 signaling between CPT1C+CAFs and M2-like phenotype of macrophage and identified CPT1C+CAFs as the primary source of IL-6. Meanwhile, suppressing CPT1C expression in CAFs significantly decreased IL-6 secretion in vitro. Lastly, we demonstrated the association of CPT1C+CAFs with therapeutic resistance. Notably, GC patients with high CPT1C+CAFs infiltration responded poorly to immunotherapy in clinical cohort. Collectively, our data not only present the novel identification of CPT1C+CAFs as immunosuppressive subsets in TME of GC, but also reveal the underlying mechanism that CPT1C+CAFs impair tumor immunity by secreting IL-6 to induce the immunosuppressive M2-like phenotype of macrophage in GC.


Assuntos
Fibroblastos Associados a Câncer , Carnitina O-Palmitoiltransferase , Interleucina-6 , Macrófagos , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Interleucina-6/metabolismo , Interleucina-6/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Fenótipo , Animais , Camundongos , Masculino , Feminino , Linhagem Celular Tumoral , Tolerância Imunológica
9.
FASEB J ; 38(11): e23709, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38809700

RESUMO

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.


Assuntos
Tecido Adiposo Marrom , Fibrose , Proteína Desacopladora 1 , Animais , Tecido Adiposo Marrom/metabolismo , Camundongos , Masculino , Proteína Desacopladora 1/metabolismo , Fibrose/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Camundongos Endogâmicos C57BL , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Fisiológico , Remodelação Ventricular/fisiologia , Camundongos Knockout , Temperatura Baixa
10.
Chem Biol Drug Des ; 103(5): e14532, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38725089

RESUMO

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that causes severe liver damage, fibrosis, and scarring. Despite its potential to progress to cirrhosis or hepatic failure, approved drugs or treatments are currently unavailable. We developed 4,4-diallyl curcumin bis(2,2-hydroxymethyl)propanoate, also known as 35e, which induces upregulation of mitochondrial proteins including carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II, heat shock protein 60, and translocase of the outer mitochondrial membrane 20. Among these proteins, the upregulated expression of CPT-I was most prominent. CPT-I plays a crucial role in transporting carnitine across the mitochondrial inner membrane, thereby initiating mitochondrial ß-oxidation of fatty acids. Given recent research showing that CPT-I activation could be a viable pathway for NASH treatment, we hypothesized that 35e could serve as a potential agent for treating NASH. The efficacy of 35e in treating NASH was evaluated in methionine- and choline-deficient (MCD) diet- and Western diet (WD)-induced models that mimic human NASH. In the MCD diet-induced model, both short-term (2 weeks) and long-term (7 weeks) treatment with 35e effectively regulated elevated serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) concentrations and histological inflammation. However, the antisteatotic effect of 35e was obtained only in the short-term treatment group. As a comparative compound in the MCD diet-induced model, curcumin treatment did not produce significant regulatory effects on the liver triglyceride/total cholesterol, serum ALT/AST, or hepatic steatosis. In the WD-induced model, 35e ameliorated hepatic steatosis and hepatic inflammation, while increasing serum AST and hepatic lipid content. A decrease in epididymal adipose tissue weight and serum free fatty acid concentration suggested that 35e may promote lipid metabolism or impede lipid accumulation. Overall, 35e displayed significant antilipid accumulation and antifibrotic effects in the two complementary mice models. The development of new curcumin derivatives with the ability to induce CPT-I upregulation could further underscore their efficacy as anti-NASH agents.


Assuntos
Curcumina , Modelos Animais de Doenças , Metionina , Hepatopatia Gordurosa não Alcoólica , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Metionina/metabolismo , Metionina/deficiência , Curcumina/farmacologia , Curcumina/química , Curcumina/uso terapêutico , Camundongos , Masculino , Dieta Ocidental/efeitos adversos , Camundongos Endogâmicos C57BL , Carnitina O-Palmitoiltransferase/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Propionatos/farmacologia , Propionatos/uso terapêutico , Propionatos/metabolismo , Humanos , Colina/metabolismo , Colina/farmacologia
11.
Nutrients ; 16(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38732512

RESUMO

Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid markers for RCC remain unidentified. We aimed to discover and validate potent plasma markers and their association with dietary fats. Using lipid metabolite quantification, machine-learning algorithms, and marker validation, we identified RCC diagnostic markers in studies involving 60 RCC and 167 healthy controls (HC), as well as 27 RCC and 74 HC, by analyzing their correlation with dietary fats. RCC was associated with altered metabolism in amino acids, glycerophospholipids, and glutathione. We validated seven markers (l-tryptophan, various lysophosphatidylcholines [LysoPCs], decanoylcarnitine, and l-glutamic acid), achieving a 96.9% AUC, effectively distinguishing RCC from HC. Decreased decanoylcarnitine, due to reduced carnitine palmitoyltransferase 1 (CPT1) activity, was identified as affecting RCC risk. High intake of polyunsaturated fatty acids (PUFAs) was negatively correlated with LysoPC (18:1) and LysoPC (18:2), influencing RCC risk. We validated seven potential markers for RCC diagnosis, highlighting the influence of high PUFA intake on LysoPC levels and its impact on RCC occurrence via CPT1 downregulation. These insights support the efficient and accurate diagnosis of RCC, thereby facilitating risk mitigation and improving patient outcomes.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Estudos de Casos e Controles , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Idoso , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/sangue , Carnitina O-Palmitoiltransferase/metabolismo , Adulto , Lisofosfatidilcolinas/sangue , Carnitina/sangue , Carnitina/análogos & derivados , Aprendizado de Máquina , Metabolismo dos Lipídeos , Triptofano/sangue
12.
Cell Commun Signal ; 22(1): 283, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783346

RESUMO

BACKGROUND: In addition to functioning as a precise monitoring mechanism in cell cycle, the anaphase-promoting complex/cyclosome (APC/C) is reported to be involved in regulating multiple metabolic processes by facilitating the ubiquitin-mediated degradation of key enzymes. Fatty acid oxidation is a metabolic pathway utilized by tumor cells that is crucial for malignant progression; however, its association with APC/C remains to be explored. METHODS: Cell cycle synchronization, immunoblotting, and propidium iodide staining were performed to investigate the carnitine palmitoyltransferase 1 C (CPT1C) expression manner. Proximity ligation assay and co-immunoprecipitation were performed to detect interactions between CPT1C and APC/C. Flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium, inner salt (MTS) assays, cell-scratch assays, and transwell assays and xenograft transplantation assays were performed to investigate the role of CPT1C in tumor progression in vitro and in vivo. Immunohistochemistry was performed on tumor tissue microarray to evaluate the expression levels of CPT1C and explore its potential clinical value. RESULTS: We identified CPT1C as a novel APC/C substrate. CPT1C protein levels exhibited cell cycle-dependent fluctuations, peaking at the G1/S boundary. Elevated CPT1C accelerated the G1/S transition, facilitating tumor cell proliferation in vitro and in vivo. Furthermore, CPT1C enhanced fatty acid utilization, upregulated ATP levels, and decreased reactive oxygen species levels, thereby favoring cell survival in a harsh metabolic environment. Clinically, high CPT1C expression correlated with poor survival in patients with esophageal squamous cell carcinoma. CONCLUSIONS: Overall, our results revealed a novel interplay between fatty acid utilization and cell cycle machinery in tumor cells. Additionally, CPT1C promoted tumor cell proliferation and survival by augmenting cellular ATP levels and preserving redox homeostasis, particularly under metabolic stress. Therefore, CPT1C could be an independent prognostic indicator in esophageal squamous cell carcinoma.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase , Carnitina O-Palmitoiltransferase , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Humanos , Animais , Linhagem Celular Tumoral , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Ciclossomo-Complexo Promotor de Anáfase/genética , Metabolismo Energético/genética , Regulação para Cima , Progressão da Doença , Proliferação de Células , Camundongos Nus , Camundongos , Feminino , Masculino , Fase S , Camundongos Endogâmicos BALB C
13.
Nat Commun ; 15(1): 4469, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796472

RESUMO

To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2L-/- mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.


Assuntos
Carnitina O-Palmitoiltransferase , Jejum , Hepatócitos , Homeostase , Metabolismo dos Lipídeos , Fígado , Camundongos Knockout , Proteínas rab de Ligação ao GTP , Animais , Masculino , Camundongos , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Colesterol/metabolismo , Jejum/metabolismo , Complexo de Golgi/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Triglicerídeos/metabolismo , Triglicerídeos/sangue
14.
Adv Sci (Weinh) ; 11(24): e2308945, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38627980

RESUMO

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.


Assuntos
Ácidos Graxos , Oxirredução , Fator de Transcrição STAT3 , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Camundongos , Feminino , Ácidos Graxos/metabolismo , Humanos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Camundongos Knockout , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
15.
Exp Cell Res ; 438(1): 114031, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38616032

RESUMO

Diabetes is closely associated with vascular calcification (VC). Exorbitant glucose concentration activates pro-calcific effects in vascular smooth muscle cells (VSMCs). This study enrolled 159 elderly patients with type 2 diabetes and divided them into three groups, T1, T2 and T3, according to brachial-ankle pulse wave velocity(BaPWV). There were statistically significant differences in the waist circumference, waist hip ratio, systolic blood pressure, 12,13-diHOME (a lipokin) concentration among T1, T2 and T3. 12,13-diHOME levels were positively correlated to high density lipoprotein cholesterol and total cholesterol, but negatively correlated to with waist circumference, waist hip ratio, systolic blood pressure and baPWV. Studies in vitro showed that 12,13-diHOME effectively inhibits calcification in VSMCs under high glucose conditions. Notably, 12,13-diHOME suppressed the up-regulation of carnitine O-palmitoyltransferase 1 (CPT1A) and CPT1A-induced succinylation of HMGB1. The succinylation of HMGB1 at the K90 promoted the protein stability and induced the enrichment of HMGB1 in cytoplasm, which induced the calcification in VSMCs. Together, 12,13-diHOME attenuates high glucose-induced calcification in VSMCs through repressing CPT1A-mediated HMGB1 succinylation.


Assuntos
Carnitina O-Palmitoiltransferase , Glucose , Proteína HMGB1 , Músculo Liso Vascular , Miócitos de Músculo Liso , Calcificação Vascular , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Proteína HMGB1/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Masculino , Idoso , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Feminino , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Cultivadas
16.
Am J Physiol Endocrinol Metab ; 326(5): E681-E695, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38597829

RESUMO

Hypothalamic proopiomelanocortin (POMC) neurons are sensors of signals that reflect the energy stored in the body. Inducing mild stress in proopiomelanocortin neurons protects them from the damage promoted by the consumption of a high-fat diet, mitigating the development of obesity; however, the cellular mechanisms behind these effects are unknown. Here, we induced mild stress in a proopiomelanocortin neuron cell line by inhibiting Crif1. In proopiomelanocortin neurons exposed to high levels of palmitate, the partial inhibition of Crif1 reverted the defects in mitochondrial respiration and ATP production; this was accompanied by improved mitochondrial fusion/fission cycling. Furthermore, the partial inhibition of Crif1 resulted in increased reactive oxygen species production, increased fatty acid oxidation, and reduced dependency on glucose for mitochondrial respiration. These changes were dependent on the activity of CPT-1. Thus, we identified a CPT-1-dependent metabolic shift toward greater utilization of fatty acids as substrates for respiration as the mechanism behind the protective effect of mild stress against palmitate-induced damage of proopiomelanocortin neurons.NEW & NOTEWORTHY Saturated fats can damage hypothalamic neurons resulting in positive energy balance, and this is mitigated by mild cellular stress; however, the mechanisms behind this protective effect are unknown. Using a proopiomelanocortin cell line, we show that under exposure to a high concentration of palmitate, the partial inhibition of the mitochondrial protein Crif1 results in protection due to a metabolic shift warranted by the increased expression and activity of the mitochondrial fatty acid transporter CPT-1.


Assuntos
Carnitina O-Palmitoiltransferase , Proteínas de Ciclo Celular , Ácidos Graxos , Mitocôndrias , Animais , Camundongos , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Linhagem Celular , Ácidos Graxos/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo
17.
Environ Pollut ; 350: 123971, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38641033

RESUMO

Haloacetaldehyde disinfection by-products (HAL-DBPs) are among the top three unregulated DBPs found in drinking water. The cytotoxicity and genotoxicity of HALs are much higher than that of the regulated trihalomethanes and haloacetic acids. Previous studies have mainly focused on the toxic effects of single HAL, with few examining the toxic effects of mixed exposures to HALs. The study aimed to observe the effects of mixed exposures of 1∼1000X the realistic level of HALs on the hepatotoxicity and lipid metabolism of C57BL/6J mice, based on the component and concentration of HALs detected in the finished water of Shanghai. Exposure to realistic levels of HALs led to a significant increase in phosphorated acetyl CoA carboxylase 1 (p-ACC1) in the hepatic de novo lipogenesis (DNL) pathway. Additionally, exposure to 100X realistic levels of HALs resulted in significant alterations to key enzymes of DNL pathway, including ACC1, fatty acid synthase (FAS), and diacylglycerol acyltransferase 2 (DGAT2), as well as key proteins of lipid disposal such as carnitine palmitoyltransferase 1 (CPT-1) and peroxisome proliferator activated receptor α (PPARα). Exposure to 1000X realistic levels of HALs significantly increased hepatic and serum triglyceride levels, as well as total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate transaminase, alkaline phosphatase, and lactate dehydrogenase levels, significantly decreased high-density lipoprotein. Meanwhile, histopathological analysis demonstrated that HALs exacerbated tissue vacuolization and inflammatory cell infiltration in mice livers, which showed the typical phenotypes of non-alcoholic fatty liver disease (NAFLD). These results suggested that the HALs mixture is a critical risk factor for NAFLD and is significantly highly toxic to C57BL/6J mice.


Assuntos
Acetaldeído , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , Animais , Camundongos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Acetaldeído/toxicidade , Acetaldeído/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Desinfecção , Poluentes Químicos da Água/toxicidade , Acetil-CoA Carboxilase/metabolismo , PPAR alfa/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Diacilglicerol O-Aciltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Lipogênese/efeitos dos fármacos , Desinfetantes/toxicidade , Ácido Graxo Sintases/metabolismo , China , Água Potável/química
18.
Artigo em Inglês | MEDLINE | ID: mdl-38657943

RESUMO

In mammals, physiological processes related to lipid metabolism, such as chylomicron synthesis or fatty acid oxidation (FAO), modulate eating, highlighting the importance of energostatic mechanisms in feeding control. This study, using rainbow trout (Oncorhynchus mykiss) as model, aimed to characterize the role of FAO and chylomicron formation as peripheral lipid sensors potentially able to modulate feeding in fish. Fish fed with either a normal- (24%) or high- (32%) fat diet were intraperitoneally injected with water alone or containing etomoxir (inhibitor of FAO rate-limiting enzyme carnitine palmitoyl-transferase 1). First, feed intake levels were recorded. We observed an etomoxir-derived decrease in feeding at short times, but a significant increase at 48 h after treatment in fish fed normal-fat diet. Then, we evaluated putative etomoxir effects on the mRNA abundance of genes related to lipid metabolism, chylomicron synthesis and appetite-regulating peptides. Etomoxir treatment upregulated mRNA levels of genes related to chylomicron assembly in proximal intestine, while opposite effects occurred in distal intestine, indicating a clear regionalization in response. Etomoxir also modulated gastrointestinal hormone mRNAs in proximal intestine, upregulating ghrl in fish fed normal-fat diet and pyy and gcg in fish fed high-fat diet. These results provide evidence for an energostatic control of feeding related to FAO and chylomicron formation at the peripheral level in fish.


Assuntos
Quilomícrons , Gorduras na Dieta , Ácidos Graxos , Metabolismo dos Lipídeos , Oncorhynchus mykiss , Oxirredução , Animais , Oncorhynchus mykiss/metabolismo , Ácidos Graxos/metabolismo , Quilomícrons/metabolismo , Gorduras na Dieta/metabolismo , Gorduras na Dieta/farmacologia , Trato Gastrointestinal/metabolismo , Compostos de Epóxi/metabolismo , Compostos de Epóxi/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética
19.
Diabetes ; 73(6): 879-895, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38506804

RESUMO

Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from patients with diabetes. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment.


Assuntos
Apoptose , Carnitina O-Palmitoiltransferase , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Podócitos , Animais , Humanos , Masculino , Camundongos , Albuminúria/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Ácidos Graxos/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Podócitos/metabolismo , Podócitos/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética
20.
Aging (Albany NY) ; 16(5): 4591-4608, 2024 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-38428407

RESUMO

BACKGROUND: Excessive lipids accumulation and hepatocytes death are prominent characteristics of non-alcoholic fatty liver disease (NAFLD). Nonetheless, the precise pathophysiological mechanisms are not fully elucidated. METHODS: HepG2 cells stimulated with palmitic acids and rats fed with high-fat diet were used as models for NAFLD. The impact of Glucosylceramidase Beta 3 (GBA3) on fatty acid oxidation (FAO) was assessed using Seahorse metabolic analyzer. Lipid content was measured both in vitro and in vivo. To evaluate NAFLD progression, histological analysis was performed along with measurements of inflammatory factors and liver enzyme levels. Western blot and immunohistochemistry were employed to examine the activity levels of necroptosis. Flow cytometry and reactive oxygen species (ROS) staining were utilized to assess levels of oxidative stress. RESULTS: GBA3 promoted FAO and enhanced the mitochondrial membrane potential without affecting glycolysis. These reduced the lipid accumulation. Rats supplemented with GBA3 exhibited lower levels of inflammatory factors and liver enzymes, resulting in a slower progression of NAFLD. GBA3 overexpression reduced ROS and the ratio of cell apoptosis. Phosphorylation level was reduced in the essential mediator, MLKL, implicated in necroptosis. Mechanistically, as a transcriptional coactivator, GBA3 promoted the expression of Carnitine Palmitoyltransferase 2 (CPT2), which resulted in enhanced FAO. CONCLUSIONS: Increased FAO resulting from GBA3 reduced oxidative stress and the production of ROS, thereby inhibiting necroptosis and delaying the progression of NAFLD. Our research offers novel insights into the potential therapeutic applications of GBA3 and FAO in the management and treatment of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Glucosilceramidase , Metabolismo dos Lipídeos , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Lipídeos
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