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1.
Life Sci ; 350: 122763, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38823505

RESUMO

AIMS: The intricate molecular mechanisms underlying estrogen receptor-positive (ER+) breast carcinogenesis and resistance to endocrine therapy remain elusive. In this study, we elucidate the pivotal role of GPR81, a G protein-coupled receptor, in ER+ breast cancer (BC) by demonstrating low expression of GPR81 in tamoxifen (TAM)-resistant ER+ BC cell lines and tumor samples, along with the underlying molecular mechanisms. MAIN METHODS: Fatty acid oxidation (FAO) levels and lipid accumulation were explored using MDA and FAßO assay, BODIPY 493/503 staining, and Lipid TOX staining. Autophagy levels were assayed using CYTO-ID detection and Western blotting. The impact of GPR81 on TAM resistance in BC was investigated through CCK8 assay, colony formation assay and a xenograft mice model. RESULTS: Aberrantly low GPR81 expression in TAM-resistant BC cells disrupts the Rap1 pathway, leading to the upregulation of PPARα and CPT1. This elevation in PPARα/CPT1 enhances FAO, impedes lipid accumulation and lipid droplet (LD) formation, and subsequently inhibits cell autophagy, ultimately promoting TAM-resistant BC cell growth. Moreover, targeting GPR81 and FAO emerges as a promising therapeutic strategy, as the GPR81 agonist and the CPT1 inhibitor etomoxir effectively inhibit ER+ BC cell and tumor growth in vivo, re-sensitizing TAM-resistant ER+ cells to TAM treatment. CONCLUSION: Our data highlight the critical and functionally significant role of GPR81 in promoting ER+ breast tumorigenesis and resistance to endocrine therapy. GPR81 and FAO levels show potential as diagnostic biomarkers and therapeutic targets in clinical settings for TAM-resistant ER+ BC.


Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Ácidos Graxos , Camundongos Nus , Oxirredução , PPAR alfa , Receptores Acoplados a Proteínas G , Tamoxifeno , Tamoxifeno/farmacologia , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Receptores Acoplados a Proteínas G/metabolismo , Animais , Ácidos Graxos/metabolismo , Camundongos , PPAR alfa/metabolismo , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Autofagia/efeitos dos fármacos , Camundongos Endogâmicos BALB C
2.
Food Res Int ; 188: 114489, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823872

RESUMO

Solanum nigrum L. (SN) berry is an edible berry containing abundant polyphenols and bioactive compounds, which possess antioxidant and antiinflammatory properties. However, the effects of SN on alcohol-induced biochemical changes in the enterohepatic axis remain unclear. In the current study, a chronic ethanol-fed mice ALD model was used to test the protective mechanisms of SN berries. Microbiota composition was determined via 16S rRNA sequencing, we found that SN berries extract (SNE) improved intestinal imbalance by reducing the Firmicutes to Bacteroides ratio, restoring the abundance of Akkermansia microbiota, and reducing the abundance of Allobaculum and Shigella. SNE restored the intestinal short-chain fatty acids content. In addition, liver transcriptome data analysis revealed that SNE primarily affected the genes involved in lipid metabolism and inflammatory responses. Furthermore, SNE ameliorated hepatic steatosis in alcohol-fed mice by activating AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), peroxisome proliferator-activated receptor α (PPAR-α). SNE reduced the expression of toll-like receptor 4 (TLR4), myeloid differentiation factor-88 (MyD88) nuclear factor kappa-B (NF-κB), which can indicate that SNE mainly adjusted LPS/TLR4/MyD88/NF-κB pathway to reduce liver inflammation. SNE enhanced hepatic antioxidant capacity by regulating NRF2-related protein expression. SNE alleviates alcoholic liver injury by regulating of gut microbiota, lipid metabolism, inflammation, and oxidative stress. This study may provide a reference for the development and utilization of SN resources.


Assuntos
Frutas , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Hepatopatias Alcoólicas , Estresse Oxidativo , Extratos Vegetais , Solanum nigrum , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Camundongos , Frutas/química , Solanum nigrum/química , Masculino , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/prevenção & controle , Camundongos Endogâmicos C57BL , Inflamação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptor 4 Toll-Like/metabolismo , Modelos Animais de Doenças , PPAR alfa/metabolismo , Antioxidantes/farmacologia , Etanol
3.
Sci Rep ; 14(1): 13435, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862650

RESUMO

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal ß-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased ß-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.


Assuntos
Córnea , Diabetes Mellitus Experimental , Neuropatias Diabéticas , Fenofibrato , PPAR alfa , Animais , PPAR alfa/agonistas , PPAR alfa/metabolismo , Camundongos , Fenofibrato/farmacologia , Fenofibrato/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Córnea/metabolismo , Córnea/efeitos dos fármacos , Córnea/inervação , Córnea/patologia , Masculino , Administração Oral , Administração Tópica , Doenças da Córnea/tratamento farmacológico , Doenças da Córnea/etiologia , Doenças da Córnea/metabolismo , Doenças da Córnea/patologia , Camundongos Endogâmicos C57BL , Proteômica/métodos
4.
Biomed Pharmacother ; 176: 116908, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38850668

RESUMO

Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the therapeutic effects and potential mechanism of a novel extract from traditional Chinese medicine Alisma orientale (Sam.) Juzep (AE) on free fatty acid (FFA)-induced HepG2 cell model and high-fat diet (HFD) + carbon tetrachloride (CCl4)-induced mouse model of NASH. C57BL/6 J mice were fed a HFD for 10 weeks. Subsequently, the mice were injected with CCl4 to induce NASH and simultaneously treated with AE at daily doses of 50, 100, and 200 mg/kg for 4 weeks. At the end of the treatment, animals were fasted for 12 h and then sacrificed. Blood samples and liver tissues were collected for analysis. Lipid profiles, oxidative stress, and histopathology were examined. Additionally, a polymerase chain reaction (PCR) array was used to predict the molecular targets and potential mechanisms involved, which were further validated in vivo and in vitro. The results demonstrated that AE reversed liver damage (plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte ballooning, hepatic steatosis, and NAS score), the accumulation of hepatic lipids (TG and TC), and oxidative stress (MDA and GSH). PCR array analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that AE protects against NASH by regulating the adipocytokine signaling pathway and influencing nuclear receptors such as PPARα. Furthermore, AE increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1α) and reversed the decreased expression of PPARα in NASH mice. Moreover, in HepG2 cells, AE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. Overall, our findings suggest that AE may serve as a potential therapeutic approach for NASH by inhibiting lipid accumulation and reducing oxidative stress specifically through the PPARα pathway.


Assuntos
Alisma , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , PPAR alfa , Extratos Vegetais , Transdução de Sinais , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Humanos , Alisma/química , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificação , Células Hep G2 , Dieta Hiperlipídica/efeitos adversos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Modelos Animais de Doenças , Tetracloreto de Carbono , Metabolismo dos Lipídeos/efeitos dos fármacos
5.
Physiol Rep ; 12(12): e16117, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38898524

RESUMO

This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O2 [10 min] and 30% O2 [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor-A (BF ≥10), PPAR-α (BF ≥3), and PPAR-γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise-trained (ET) group. INT group exhibited significantly higher activity levels of 3-hydroxyacyl-CoA-dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT-PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.


Assuntos
Músculo Esquelético , Condicionamento Físico Animal , Resistência Física , Animais , Masculino , Músculo Esquelético/metabolismo , Camundongos , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia , Resistência Física/fisiologia , Camundongos Endogâmicos C57BL , Hiperóxia/metabolismo , Hiperóxia/fisiopatologia , PPAR alfa/metabolismo , PPAR alfa/genética , PPAR gama/metabolismo , PPAR gama/genética , Fosfofrutoquinases/metabolismo , Fosfofrutoquinases/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA , Proteínas Mitocondriais
6.
Clin Nutr ; 43(6): 1475-1487, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38723301

RESUMO

BACKGROUND & AIMS: The past few decades have witnessed a rapid growth in the prevalence of nonalcoholic fatty liver disease (NAFLD). While the ketogenic diet (KD) is considered for managing NAFLD, the safety and efficacy of the KD on NAFLD has been a controversial topic. Here, we aimed to investigate the effect of KD of different durations on metabolic endpoints in mice with NAFLD and explore the underlying mechanisms. METHODS: NAFLD mice were fed with KD for 1, 2, 4 and 6 weeks, respectively. The blood biochemical indexes (blood lipids, AST, ALT and etc.) and liver fat were measured. The LC-MS/MS based proteomic analysis was performed on liver tissues. Metallothionein-2 (MT2) was knocked down with adeno-associated virus (AAV) or small interfering RNA (siRNA) in NAFLD mice and AML-12 cells, respectively. H&E, BODIPY and ROS staining were performed to examine lipid deposition and oxidative stress. Furthermore, MT2 protein levels, nucleus/cytoplasm distribution and DNA binding activity of peroxisome proliferators-activated receptors α (PPARα) were evaluated. RESULTS: KD feeding for 2 weeks showed the best improvement on NAFLD phenotype. Proteomic analysis revealed that MT2 was a key candidate for different metabolic endpoints of NAFLD affected by different durations of KD feeding. MT2 knockdown in NAFLD mice blocked the effects of 2 weeks of KD feeding on HFD-induced steatosis. In mouse primary hepatocytes and AML-12 cells, MT2 protein levels were induced by ß-hydroxybutyric acid (ß-OHB). MT2 Knockdown blunted the effects of ß-OHB on alleviating PA-induced lipid deposition. Mechanistically, 2 weeks of KD or ß-OHB treatment reduced oxidative stress and upregulated the protein levels of MT2 in nucleus, which subsequently increased its DNA binding activity and PPARα protein expression. CONCLUSIONS: Collectively, these findings indicated that KD feeding prevented NAFLD in a time dependent manner and MT2 is a potential target contributing to KD improvement on steatosis.


Assuntos
Dieta Cetogênica , Metalotioneína , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Regulação para Cima , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/genética , Metalotioneína/genética , Metalotioneína/metabolismo , Dieta Cetogênica/métodos , Camundongos , Masculino , Fígado/metabolismo , Antioxidantes/metabolismo , PPAR alfa/metabolismo , PPAR alfa/genética , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Fatores de Tempo
7.
Cell Metab ; 36(6): 1371-1393.e7, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38718791

RESUMO

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer.


Assuntos
Carcinoma Hepatocelular , Jejum , Neoplasias Hepáticas , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , PPAR alfa , Fosfoenolpiruvato Carboxiquinase (GTP) , PPAR alfa/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Humanos , Camundongos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Masculino , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Transdução de Sinais , Jejum Intermitente
8.
J Ethnopharmacol ; 331: 118282, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38701935

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Sang Yu granule (SY), a traditional Chinese medicine prescription of Xijing Hospital, was developed based on the Guanyin powder in the classical prescription "Hong's Collection of Proven Prescriptions" and the new theory of modern Chinese medicine. It has been proved to have a certain therapeutic effect on drug-induced liver injury (DILI), but the specific mechanism of action is still unclear. AIM OF STUDY: Aim of the study was to explore the effect of SangYu granule on treating drug-induced liver injury induced by acetaminophen in mice. MATERIALS AND METHODS: The chemical composition of SY, serum, and liver tissue was analyzed using ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry. To assess hepatic function, measurements were taken using kits for total bile acids, as well as serum AST, ALT, and ALP activity. Concentrations of IL-1ß and TNF-α in serum were quantified using ELISA kits. Transcriptome Sequencing Analysis and 2bRAD-M microbial diversity analysis were employed to evaluate gene expression variance in liver tissue and fecal microbiota diversity among different groups, respectively. Western blotting was performed to observe differences in the activation levels of FXR, SHP, CYP7A1 and PPARα in the liver, and the levels of FXR and FGF-15 genes and proteins in the ileum of mice. Additionally, fecal microbiota transplantation (FMT) experiments were conducted to investigate the potential therapeutic effect of administering the intestinal microbial suspension from mice treated with SY on drug-induced liver injury. RESULTS: SY treatment exhibited significant hepatoprotective effects in mice, effectively ameliorating drug-induced liver injury while concurrently restoring intestinal microbial dysbiosis. Furthermore, SY administration demonstrated a reduction in the concentration of total bile acids, the expression of FXR and SHP proteins in the liver was up-regulated, CYP7A1 protein was down-regulated, and the expressions of FXR and FGF-15 proteins in the ileum were up-regulated. However, no notable impact on PPARα was observed. Furthermore, results from FMT experiments indicated that the administration of fecal suspensions derived from mice treated with SY did not yield any therapeutic benefits in the context of drug-induced liver injury. CONCLUSION: The aforementioned findings strongly suggest that SY exerts a pronounced ameliorative effect on drug-induced liver injury through its ability to modulate the expression of key proteins involved in bile acid secretion, thereby preserving hepato-enteric circulation homeostasis.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Fígado , PPAR alfa , Animais , Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , PPAR alfa/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos , Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/sangue , Ácidos e Sais Biliares/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética
9.
Anal Chim Acta ; 1309: 342666, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38772654

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors and represent the targets for the therapeutical treatment of type 2 diabetes, dyslipidemia and hyperglycemia associated with metabolic syndrome. Some medicinal plants have been traditionally used to treat this kind of metabolic diseases. Today only few drugs targeting PPARs have been approved and for this reason, the rapid identification of novel ligands and/or chemical scaffolds starting from natural extracts would benefit of a selective affinity ligand fishing assay. RESULTS: In this paper we describe the development of a new ligand fishing assay based on size exclusion chromatography (SEC) coupled to LC-MS for the analysis of complex samples such as botanical extracts. The known PPARα and PPARγ ligands, WY-14643 and rosiglitazone respectively, were used for system development and evaluation. The system has found application on an Allium lusitanicum methanolic extract, containing saponins, a class of chemical compounds which have attracted interest as PPARs ligands because of their hypolipidemic and insulin-like properties. SIGNIFICANCE: A new SEC-AS-MS method has been developed for the affinity screening of PPARα and PPARγ ligands. The system proved to be highly specific and will be used to improve the throughput for the identification of new selective metabolites from natural souces targeting PPARα and PPARγ.


Assuntos
Cromatografia em Gel , PPAR alfa , PPAR gama , Extratos Vegetais , PPAR gama/metabolismo , PPAR gama/química , PPAR alfa/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ligantes , Espectrometria de Massas , Rosiglitazona/farmacologia , Rosiglitazona/química , Humanos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/análise , Pirimidinas
10.
Food Funct ; 15(11): 5955-5971, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38738998

RESUMO

The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that Laminaria japonica- and Ascophyllum nodosum-derived fucoidans have type I and type II fucosyl chains, respectively. These chemical differences may contribute to distinct hypolipidemic effects and mechanisms of action. Chemical analysis demonstrated that the percentage contents of sulfate, glucuronic acid, and galactose were higher in L. japonica-derived fucoidans than those of A. nodosum-derived fucoidans. In hyperlipidemic apolipoprotein E-deficient mice, both A. nodosum- and L. japonica-derived fucoidans significantly decreased the plasma and hepatic levels of total cholesterol and triglyceride, leading to the reduction of atherosclerotic plaques. Western blotting experiments demonstrated that these fucoidans significantly enhanced the expression and levels of scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, and peroxisome proliferator-activated receptor (PPAR)-α, contributing to circulating lipoprotein clearance and fatty acid degradation, respectively. Differentially, L. japonica-derived fucoidan significantly increased the LXR/ATP-binding cassette G8 signaling pathway in the small intestine, as revealed by real-time quantitative PCR, which may lead to further cholesterol and other lipid excretion. Collectively, these data are useful for understanding the hypolipidemic mechanisms of action of seaweed-derived fucoidans, and their potential application for the prevention and/or treatment of atherosclerotic cardiovascular diseases.


Assuntos
Apolipoproteínas E , Ascophyllum , Hipolipemiantes , Laminaria , Polissacarídeos , Animais , Laminaria/química , Ascophyllum/química , Camundongos , Polissacarídeos/farmacologia , Polissacarídeos/química , Hipolipemiantes/farmacologia , Apolipoproteínas E/genética , Masculino , Camundongos Endogâmicos C57BL , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Colesterol/sangue , Colesterol/metabolismo , Camundongos Knockout , PPAR alfa/metabolismo , PPAR alfa/genética , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Fígado/metabolismo , Fígado/efeitos dos fármacos , Humanos , Algas Comestíveis
11.
Exp Biol Med (Maywood) ; 249: 10141, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711461

RESUMO

Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death. Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions. In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl4) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses. The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α. In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl4-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.


Assuntos
Canabidiol , Tetracloreto de Carbono , Cirrose Hepática , NF-kappa B , PPAR alfa , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , NF-kappa B/metabolismo , PPAR alfa/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Camundongos , Tetracloreto de Carbono/toxicidade , Masculino , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo
12.
Transl Res ; 271: 26-39, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38734063

RESUMO

Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence 'YEVEDYR') from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to ß-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.


Assuntos
Doxorrubicina , Fibroínas , Metabolismo dos Lipídeos , PPAR alfa , Proteína 2 Glutamina gama-Glutamiltransferase , Animais , PPAR alfa/metabolismo , PPAR alfa/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fibroínas/química , Fibroínas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Peptídeos/farmacologia , Peptídeos/química , Ratos , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos Sprague-Dawley
13.
Diabetes Res Clin Pract ; 212: 111688, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697298

RESUMO

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARß/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.


Assuntos
Diabetes Mellitus Tipo 2 , Receptores Ativados por Proliferador de Peroxissomo , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fígado Gorduroso/tratamento farmacológico , Resistência à Insulina/fisiologia , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Animais
14.
Neuropharmacology ; 254: 109988, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38744401

RESUMO

Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.


Assuntos
Camundongos Endogâmicos C57BL , Neuralgia , PPAR alfa , Medula Espinal , Animais , PPAR alfa/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Masculino , Camundongos , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Metabolômica , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos
15.
Toxicol Lett ; 397: 79-88, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734220

RESUMO

The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.


Assuntos
Proliferação de Células , Hepatócitos , Hepatomegalia , Fígado , Camundongos Endogâmicos C57BL , PPAR alfa , Receptor de Pregnano X , Pirimidinas , Proteínas de Sinalização YAP , Animais , PPAR alfa/agonistas , PPAR alfa/metabolismo , Hepatomegalia/induzido quimicamente , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Receptor de Pregnano X/metabolismo , Receptor de Pregnano X/genética , Proteínas de Sinalização YAP/metabolismo , Pirimidinas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proliferação de Células/efeitos dos fármacos , beta Catenina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Citocromo P-450 CYP4A/metabolismo , Citocromo P-450 CYP4A/genética , Família 4 do Citocromo P450/genética , Família 4 do Citocromo P450/metabolismo , Camundongos , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Antígeno Ki-67/metabolismo , Proteínas de Membrana , Esteroide Hidroxilases , Família 2 do Citocromo P450 , Citocromo P-450 CYP3A , Hidrocarboneto de Aril Hidroxilases
16.
Phytomedicine ; 130: 155705, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38761776

RESUMO

BACKGROUND: Senolytic combination of dasatinib and quercetin (DQ) is the most studied senolytics drugs used to treat various age-related diseases. However, its protective activity against diabetic kidney disease (DKD) and underlying mechanisms are uncertain. PURPOSE: To investigate the functions and potential mechanisms of the senolytics DQ on DKD. METHODS: Diabetic db/db mice were administrated DQ or transfected with over-expressed PPARα or shPPARα vector. The positive control group was administered irbesartan. Renal function and fibrotic changes in kidney tissue were tested. Single-cell RNA-seq (scRNA-seq) was conducted to analyze the differential transcriptome between the diabetic and control mice. Molecular docking simulation was used to assess the combination of DQ and potential factors. Moreover, tubular epithelial cells under high-glucose (HG) conditions were incubated with DQ and transfected with or without over-expressed PPARα/siPPARα vector. RESULTS: DQ significantly improved renal function, histopathological and fibrotic changes, alleviated lipid deposition, and increased ATP levels in mice with DKD. DQ reduced multiple fatty acid oxidation (FAO) pathway-related proteins and up-regulated PPARα in db/db mice. Overexpression of PPARα upregulated the expression of PPARα-targeting downstream FAO pathway-related proteins, restored renal function, and inhibited renal fibrosis in vitro and in vivo. Moreover, molecular docking and dynamics simulation analyses indicated the nephroprotective effect of DQ via binding to PPARα. Knockdown of PPARα reversed the effect of DQ on the FAO pathway and impaired the protective effect of DQ during DKD. CONCLUSION: For the first time, DQ was found to exert a renal protective effect by binding to PPARα and attenuating renal damage through the promotion of FAO in DKD.


Assuntos
Dasatinibe , Nefropatias Diabéticas , Simulação de Acoplamento Molecular , PPAR alfa , Quercetina , Animais , Nefropatias Diabéticas/tratamento farmacológico , Quercetina/farmacologia , PPAR alfa/metabolismo , Camundongos , Dasatinibe/farmacologia , Masculino , Rim/efeitos dos fármacos , Rim/patologia , Camundongos Endogâmicos C57BL , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações
17.
Free Radic Biol Med ; 221: 81-88, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38762061

RESUMO

Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.


Assuntos
Benzamidas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Nitrilas , Estresse Oxidativo , PPAR alfa , Peroxissomos , Feniltioidantoína , Neoplasias da Próstata , Espécies Reativas de Oxigênio , Receptores Androgênicos , Masculino , Humanos , Feniltioidantoína/farmacologia , Nitrilas/farmacologia , Peroxissomos/metabolismo , Peroxissomos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Benzamidas/farmacologia , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Espécies Reativas de Oxigênio/metabolismo , PPAR alfa/metabolismo , PPAR alfa/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/farmacologia , RNA Interferente Pequeno/genética
18.
Int J Biol Macromol ; 271(Pt 2): 132584, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38795881

RESUMO

This study evaluated the regulatory effects of Astragalus membranaceus polysaccharides (AMP) on lipid metabolism disorders induced by a high-fat diet (HFD) in spotted sea bass (Lateolabrax maculatus). Compared with the normal diets (10 % lipids), diets containing 15 % lipid levels were used as the high-fat diet (HFD). Three levels of the AMP (0.06 %, 0.08 %, 0.10 %) were added in the HFD and used as experimental diets. A total of 375 spotted sea bass (average weight 3.00 ± 0.01 g) were divided into 15 tanks and deemed as 5 groups, with each tank containing 25 fish. Fish in each group were fed with different diets for 56 days. After feeding, the HFD induced lipid metabolism disorders in fish, as evidenced by elevated serum lipids, malonaldehyde levels, and more severe liver damage. The AMP alleviated the HFD-induced liver damage, as evidenced by the reduced severity of liver histological lesions and malonaldehyde levels. The low-density lipoprotein cholesterol was reduced, and the expression of FAS and PPAR-α were down and up-regulated, respectively. However, the AMP had a limited ability to affect the serum lipids and abdominal fat percentage. These results reveal the potential of the AMP used in aquaculture to regulate lipid metabolism disorders induced by the HFD.


Assuntos
Astragalus propinquus , Bass , Dieta Hiperlipídica , Metabolismo dos Lipídeos , Polissacarídeos , Animais , Dieta Hiperlipídica/efeitos adversos , Polissacarídeos/farmacologia , Astragalus propinquus/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Transtornos do Metabolismo dos Lipídeos/metabolismo , Transtornos do Metabolismo dos Lipídeos/etiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , PPAR alfa/metabolismo , Lipídeos/sangue
19.
Phytomedicine ; 130: 155774, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38820659

RESUMO

BACKGROUND: Metabolic and alcohol-associated liver disease (MetALD) shows a high prevalence rate in liver patients, but there is currently no effective treatment for MetALD. As a typical edible traditional Chinese medicinal herb, the anti-inflammatory, antioxidant, and hepatoprotective properties of water extract of Chrysanthemum morifolium Ramat. (WECM) has been demonstrated. However, its therapeutic effect on MetALD and the associated mechanisms remain unclear. PURPOSE: To investigate the underlying mechanisms of WECM against MetALD. METHODS: We constructed a MetALD rat model following a high-fat & high-sucrose plus alcohol diet (HFHSAD). MetALD rats were treated with WECM at 2.1, 4.2, and 8.4 g/kg/d for six weeks. Efficacy was determined, and pathways associated with WECM against MetALD were predicted through serum and hepatic biochemical marker measurement, histopathological section analysis, 16S rDNA sequencing of the gut microbiota and untargeted serum metabolomics analyses. Changes in genes and proteins in the peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) signaling pathways were detected by RT‒PCR and Western blotting. RESULTS: WECM treatment significantly attenuated hepatic steatosis, hyperlipidemia and markers of liver injury in MetALD rats. Moreover, WECM improved vascular endothelial function, hypertension, and systematic oxidative stress. Mechanistically, WECM treatment altered the overall structure of the gut microbiota through maintaining Firmicutes/Bacteroidota ratio and reducing harmful bacterial abundances such as Clostridium, Faecalibaculum, and Herminiimonas. Notably, WECM promoted 15-deoxy-△12, 14-prostaglandin J2 (15d-PGJ2) release and further activated the PPARγ to reduce serum TNF-α, IL-1ß, and IL-6 levels. Additionally, WECM upregulated PPARα and downregulated the levels of CD36 and FABP4 to improve lipid metabolism. CONCLUSION: Our findings provide the first evidence that WECM treatment significantly improved hepatic steatosis, oxidative stress and inflammation in MetALD rats by regulating the gut microbiota and activating the 15d-PGJ2/PPARγ and PPARα signaling pathway.


Assuntos
Chrysanthemum , Microbioma Gastrointestinal , Hepatopatias Alcoólicas , PPAR alfa , PPAR gama , Ratos Sprague-Dawley , Chrysanthemum/química , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , PPAR gama/metabolismo , PPAR alfa/metabolismo , Masculino , Hepatopatias Alcoólicas/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Ratos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/farmacologia , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Estresse Oxidativo/efeitos dos fármacos
20.
Cells ; 13(10)2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38786053

RESUMO

Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated transcription factor that is a key mediator of lipid metabolism and metabolic stress in the liver. Accumulating evidence shows that PPARA regulates the expression of various protein coding and non-coding genes that modulate metabolic stress in the liver. CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3) is a DNA-binding transcription factor that belongs to the myeloid translocation gene family. Many studies have shown that CBFA2T3 is associated with acute myeloid leukemia. Especially, CBFA2T3-GLIS2 fusion is a chimeric oncogene associated with a poor survival rate in pediatric acute megakaryocytic leukemia. A previous study identified that PPARA activation promoted Cbfa2t3 induction in liver and that Cbfa2t3 may have a modulatory role in metabolic stress. However, the effect of CBFA2T3 gene expression on metabolic stress is not understood. In this study, the PPARA ligand WY14643 activated Cbfa2t3 expression in mouse liver. Glucose tolerance test and insulin tolerance test data showed that insulin resistance is increased in Cbfa2t3-/- mice compared to Cbfa2t3+/+ mice. Hepatic CBFA2T3 modulates heat shock protein family A member 1b and carbonic anhydrase 5a expression. Histology analysis revealed lipid droplet and lipid accumulation in the liver of fasting Cbfa2t3-/- mice but not Cbfa2t3+/+ mice. The expression of lipid accumulation-related genes, such as Cd36, Cidea, and Fabp1, was increased in the liver of fasting Cbfa2t3-/- mice. Especially, basal expression levels of Cidea mRNA were elevated in the liver of Cbfa2t3-/- mice compared to Cbfa2t3+/+ mice. Much higher induction of Cidea mRNA was seen in the liver of Cbfa2t3-/- mice after WY14643 administration. These results indicate that hepatic CBFA2T3 is a PPARA-sensitive gene that may modulate metabolic stress in mouse liver.


Assuntos
Jejum , Metabolismo dos Lipídeos , Fígado , PPAR alfa , Animais , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Camundongos , PPAR alfa/metabolismo , PPAR alfa/genética , Masculino , Camundongos Endogâmicos C57BL , Resistência à Insulina , Camundongos Knockout , Pirimidinas/farmacologia
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