RESUMO
We report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.
Assuntos
Chalconas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Propionatos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Chalconas/farmacologia , Diabetes Mellitus Experimental/sangue , Avaliação Pré-Clínica de Medicamentos , Lipídeos/sangue , Masculino , Camundongos , PPAR alfa/agonistas , PPAR delta/agonistas , Propionatos/farmacologia , Distribuição AleatóriaRESUMO
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4 -induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. CONCLUSION: The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms.
Assuntos
Chalconas/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , PPAR alfa/agonistas , PPAR delta/agonistas , Propionatos/uso terapêutico , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Fígado Gorduroso/prevenção & controle , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Camundongos , Hepatopatia Gordurosa não Alcoólica , PPAR alfa/uso terapêutico , PPAR delta/uso terapêutico , RatosRESUMO
The transcription factor carbohydrate-responsive element-binding protein (ChREBP) has emerged as a central regulator of lipid synthesis in liver because it is required for glucose-induced expression of the glycolytic enzyme liver-pyruvate kinase (L-PK) and acts in synergy with SREBP to induce lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Liver X receptors (LXRs) are also important regulators of the lipogenic pathway, and the recent finding that ChREBP is a direct target of LXRs and that glucose itself can bind and activate LXRs prompted us to study the role of LXRs in the induction of glucose-regulated genes in liver. Using an LXR agonist in wild-type mice, we found that LXR stimulation did not promote ChREBP phosphorylation or nuclear localization in the absence of an increased intrahepatic glucose flux. Furthermore, the induction of ChREBP, L-PK, and ACC by glucose or high-carbohydrate diet was similar in LXRalpha/beta knockout compared with wild-type mice, suggesting that the activation of these genes by glucose occurs by an LXR-independent mechanism. We used fluorescence resonance energy transfer analysis to demonstrate that glucose failed to promote the interaction of LXRalpha/beta with specific cofactors. Finally, siRNA silencing of ChREBP in LXRalpha/beta knockout hepatocytes abrogated glucose-induced expression of L-PK and ACC, further demonstrating the central role of ChREBP in glucose signaling. Taken together, our results demonstrate that glucose is required for ChREBP functional activity and that LXRs are not necessary for the induction of glucose-regulated genes in liver.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica , Glucose/metabolismo , Fígado/metabolismo , Proteínas Nucleares/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Acetil-CoA Carboxilase/genética , Transporte Ativo do Núcleo Celular , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos , Fosforilação , Piruvato Quinase/genéticaRESUMO
BACKGROUND: Chronic hypoxia-induced pulmonary hypertension is associated with increased pulmonary expression of nitric oxide synthase (NOS) enzymes. Nevertheless, some reports have indicated decreased pulmonary production of NO in the disease. To address this paradox, we determined pulmonary concentrations of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) in the hypoxia-induced pulmonary hypertension rat model. In addition, we determined whether dysregulation of the ADMA-metabolizing enzyme dimethylarginine dimethylaminohydrolase I (DDAH I) plays a role in this disease. METHODS AND RESULTS: Adult male rats were exposed for 1 week to either normoxia or hypoxia (10% oxygen). Lung tissues were used for Western blot analysis of endothelial NOS and DDAH I expression, measurement of lung NO and ADMA content, and in vitro assay of DDAH enzyme activity. Western blot analysis revealed a 1.9-fold increase in endothelial NOS protein and a 37% decrease in DDAH I protein in the lungs of hypoxia-exposed rats. Both pulmonary DDAH enzyme activity and NO content were significantly decreased in the hypoxic group (by 37% and 22%, respectively), but pulmonary ADMA concentrations were increased by 2.3-fold compared with the normoxic group. CONCLUSIONS: These data demonstrate that the rat chronic hypoxia-induced pulmonary hypertension model is associated with increased pulmonary concentrations of the NOS inhibitor ADMA. Moreover, pulmonary hypertensive rats exhibit reduced pulmonary expression and activity of the ADMA-metabolizing enzyme DDAH I. The decreased DDAH I and increased ADMA concentrations may therefore contribute to pulmonary hypertension via the competitive inhibition of pulmonary NOS enzymes.
Assuntos
Amidoidrolases/metabolismo , Arginina/análogos & derivados , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Animais , Arginina/metabolismo , Western Blotting , Doença Crônica , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Hipóxia/enzimologia , Isoenzimas/metabolismo , Pulmão/irrigação sanguínea , Pulmão/química , Pulmão/metabolismo , Masculino , Nitratos/análise , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Nitritos/análise , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE OF REVIEW: The liver X receptors (alpha and beta) are oxysterol-activated nuclear receptors. A large number of liver X receptor target genes with functions in lipid homeostasis have been identified. Increasing evidence indicates that these receptors play a beneficial role in avoiding cholesterol overload by intervening at several steps of cholesterol metabolism. In this review, we describe the most recent developments concerning their functions in cholesterol and lipid metabolism and their impact in atherogenesis. RECENT FINDINGS: Although potentially undesirable effects of liver X receptor activation on triglyceride metabolism have been observed, recent in-vivo studies confirm that the overall trend is a reduction of atherogenesis. SUMMARY: Consequently, liver X receptors are becoming therapeutic targets of great interest for the treatment of atherosclerosis, especially if their action on triglyceride and cholesterol metabolism can be dissociated and isoform-specific ligands identified.
Assuntos
Arteriosclerose/metabolismo , Extratos Hepáticos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/biossíntese , Colesterol/metabolismo , Proteínas de Ligação a DNA , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos , Triglicerídeos/metabolismoRESUMO
The liver X receptors (LXRalpha and LXRbeta) are nuclear receptor transcription factors that are activated by certain oxysterol derivatives of cholesterol. As such, LXR activity may be up-regulated by cellular lipid loading or dietary cholesterol intake. Intensive research interest in the LXRs has led to the identification of an expanding list of LXR target genes. The identity of these genes, and their response to LXR activation, indicates that the LXRs play an important role in the response to excess cholesterol, and that their activation may protect against tissue cholesterol overload. In this review, we highlight the multiple roles of the LXRs in controlling cholesterol homeostasis via their coordinated effects on cholesterol synthesis, dietary cholesterol absorption, reverse cholesterol transport, and bile acid synthesis and excretion. We discuss the therapeutic interest of developing LXR agonists, in view of their apparent protective effects against atherosclerosis. However, we also draw attention to the possible undesirable side-effects of LXR activation, and thus the potential interest of developing target gene-specific LXR agonists, or agonists that are specific for only one LXR isoform.