RESUMO
BACKGROUND: Lifestyle factors and pharmacological compounds activate genetic mechanisms that influence the development of atherosclerotic and other diseases. This article reviews studies on natural and pharmacological gene activation that promotes health and enhances longevity. RESULTS: Living habits including healthy diet and regular physical activity, and pharmacotherapy, upregulate genes encoding enzymes and apolipoprotein and ATP-binding cassette transporters, acting in metabolic processes that promote health and increase survival. Cytochrome P450-enzymes, physiological factors in maintaining cholesterol homeostasis, generate oxysterols for the elimination of surplus cholesterol. Hepatic CTP:phosphocholine cytidylyltransferase-alpha is an important regulator of plasma HDL-C level. Gene-activators produce plasma lipoprotein profile, high HDL-C, HDL2-C and HDL-C/cholesterol ratio, which is typical of low risk of atherosclerotic disease, and also of exceptional longevity together with reduced prevalence of cardiovascular, metabolic and other diseases. High HDL contributes to protection against inflammation, oxidation and thrombosis, and associates with good cognitive function in very old people. Avoiding unhealthy stress and managing it properly promotes health and increases life expectancy. CONCLUSIONS: Healthy living habits and gene-activating xenobiotics upregulate mechanisms that produce lipoprotein pattern typical of very old people and enhance longevity. Lipoprotein metabolism and large HDL2 associate with the process of living a very long life. Major future goals for health promotion are the improving of commitment to both wise lifestyle choices and drug therapy, and further the developing of new and more effective and well tolerated drugs and treatments.
Assuntos
Aterosclerose/genética , Ativação Transcricional , Saúde , Humanos , LongevidadeRESUMO
BACKGROUND: Lipoproteins are closely associated with the atherosclerotic vascular process. Elevated levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) in plasma indicate a low probability of coronary heart disease (CHD) together with enhanced longevity, and elevated levels of low-density lipoprotein-cholesterol (LDL-C) and apo B indicate an increased risk of CHD and death. Studies linking gene activation and the induction of cytochrome P450 with elevated plasma levels of apo AI and HDL-C and lowered plasma levels of LDL-C presented a new potential approach to prevent and treat atherosclerotic disease. OBJECTIVE AND METHODS: This is a review aimed at clarifying the effects of P450-enzymes and gene activation on cholesterol homeostasis, the atherosclerotic vascular process, prevention and regression of atherosclerosis and the manifestation of atherosclerotic disease, particularly CHD, the leading cause of death in the world. RESULTS: P450-enzymes maintain cellular cholesterol homeostasis. They respond to cholesterol accumulation by enhancing the generation of hydroxycholesterols (oxysterols) and activating cholesterol-eliminating mechanisms. The CYP7A1, CYP27A1, CYP46A1 and CYP3A4 enzymes generate major oxysterols that enter the circulation. The oxysterols activate-via nuclear receptors-ATP-binding cassette (ABC) A1 and other genes, leading to the elimination of excess cholesterol and protecting arteries from atherosclerosis. Several drugs and nonpharmacologic compounds are ligands for the liver X receptor, pregnane X receptor and other receptors, activate P450 and other genes involved in cholesterol elimination, prevent or regress atherosclerosis and reduce cardiovascular events. CONCLUSIONS: P450-enzymes are essential in the physiological maintenance of cholesterol balance. They activate mechanisms which eliminate excess cholesterol and counteract the atherosclerotic process. Several drugs and nonpharmacologic compounds induce P450 and other genes, prevent or regress atherosclerosis and reduce the occurrence of non-fatal and fatal CHD and other atherosclerotic diseases.
Assuntos
Aterosclerose/genética , Aterosclerose/prevenção & controle , Colesterol/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Expressão Gênica/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Apolipoproteína A-I/genética , Apolipoproteína A-I/farmacologia , Apolipoproteína A-I/uso terapêutico , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Colesterol/genética , HDL-Colesterol/genética , HDL-Colesterol/farmacologia , LDL-Colesterol/sangue , LDL-Colesterol/genética , LDL-Colesterol/farmacologia , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Sistema Enzimático do Citocromo P-450/farmacologia , Proteínas de Ligação a DNA/metabolismo , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Proteínas/farmacologia , Receptores de Superfície Celular , Tiazolidinedionas , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Núcleo Celular/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Janus Quinase 1 , Leptina , Lipase Lipoproteica/biossíntese , Lipase Lipoproteica/genética , Malato Desidrogenase/biossíntese , Malato Desidrogenase/genética , Masculino , Proteína P2 de Mielina/biossíntese , Proteína P2 de Mielina/genética , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptores para Leptina , Rosiglitazona , Fator de Transcrição STAT1 , Tiazóis/farmacologia , Transativadores/metabolismoAssuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/biossíntese , Ativação Transcricional/efeitos dos fármacos , Aterosclerose/enzimologia , Aterosclerose/genética , Sistema Enzimático do Citocromo P-450/genética , Indução Enzimática , HumanosRESUMO
Multiple factors including unhealthy living habits influence the life-maintaining functions of the endoplasmic reticulum (ER) and induce ER stress and metabolic abnormalities. The ER responds to the disturbances by activating mechanisms that increase the capacity to eliminate ER stress. This article elucidates the effects of ER activation that eliminates both ER stress and associated cardiovascular, type 2 diabetic (DM2), and other metabolic diseases. ER-activating compounds eliminate ER stress by lowering elevated cholesterol, regress atherosclerosis, decrease cardiovascular mortality, reduce blood glucose and insulin, and, together with the normalization of glucose-insulin homeostasis, remove insulin resistance, pancreatic ß-cell failure, and DM2. A deficient cytochrome P450 activity in hepatic ER leads to cholesterol accumulation that induces stress and xanthoma formation, whereas P450-activating therapy up-regulates apolipoprotein AI and LDLR genes, down-regulates apolipoprotein B gene, and produces an antiatherogenic plasma lipoprotein profile. The ER activation reduces the stress also by eliminating hepatic fat and converting saturated fatty acids (FAs) to unsaturated FAs. Cognitive processes require gene expression modification, and preclinical studies indicate that ER-activating therapy improves cognition. Promotion of healthy lifestyle choices and indicated therapies are key factors in the prevention and elimination of ER stress and associated global health problems.
Assuntos
Doenças Cardiovasculares/fisiopatologia , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Animais , Aterosclerose/fisiopatologia , Retículo Endoplasmático/efeitos dos fármacos , HumanosRESUMO
Atherosclerotic cardiovascular disease is a major health problem worldwide. This article reviews studies clarifying the effects of gene-activating agents on the atherosclerotic vascular process, the occurrence of fatal and nonfatal atherosclerotic disease, and all-cause mortality. Studies originating in the 1970s linked drug-caused gene induction and high protein and cytochrome P450 concentrations in the liver with high apolipoprotein AI (apo AI) and HDL cholesterol (HDL-C) and reduced LDL cholesterol (LDL-C) levels in plasma and presented the view that the inducers, gene-activators, have beneficial exploitable effects against atherosclerosis. The following studies have shown that P450-enzymes respond to cholesterol accumulation and act in maintaining cholesterol homeostasis and that gene-activators act against the atherosclerotic process. The compounds include drugs indicated for dyslipidemias, such as statins, fibrates, niacin and cholestyramine, as well as compounds used for other purposes, including calcium channel blockers, angiotensin receptor blockers and glitazones. The compounds generate signaling mediators such as oxysterols and eicosanoids. The gene-activators upregulate, via the activation of nuclear receptors, genes encoding proteins such as apo AI and ATP-binding cassette (ABC) A1 transporters that efflux cellular cholesterol, transport it to the liver and excrete it into bile, and prevent cholesterol absorption in the intestine. Several statins, niacin, cholestyramine, calcium channel blockers, angiotensin receptor blockers, pioglitazone and etidronate regress atherosclerosis in coronary and /or carotid arteries. Other compounds, including fibrates, phenobarbital and alcohol also have positive antiatherogenic effects. Several gene-activators reduce mortality and / or morbidity from coronary heart disease and cerebrovascular disease, and also death from any cause.
Assuntos
Aterosclerose/mortalidade , Aterosclerose/prevenção & controle , Proteína Receptora de AMP Cíclico/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Proteína Receptora de AMP Cíclico/uso terapêutico , Humanos , Tiazolidinedionas/farmacologia , Regulação para CimaRESUMO
In the early 1960s liver cytochrome P450 (P450) was known as an enzyme in drug metabolism. By the late 1970s, P450 induction was associated with elevation of plasma high-density lipoprotein cholesterol and apolipoprotein AI indicating a reduced risk of atherosclerotic disease. Later on, 57 human P450 genes have been identified. One P450 enzyme participates in cholesterol synthesis, and several others catabolize it to oxysterols and other metabolites. Oxysterols are physiological ligands specific for liver X receptors (LXRs) in the activation of ATP-binding cassette (ABC) transporter and other cholesterol-lowering genes. Elevation of cholesterol leads to an endogenous induction of P450 and consequently to enhanced generation of oxysterols and activation of genes coding proteins which efflux cholesterol out of cells, transport it to the liver, catabolize and excrete cholesterol into bile, and prevent absorption of cholesterol in the intestine in the processes that maintain cellular cholesterol homeostasis and protect arteries from atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) co-operate with LXRs and ABC transporters in cholesterol regulation. Secretion of oxysterol is a direct pathway for cellular cholesterol elimination. Several compounds induce P450 and other genes regulating cholesterol balance and prevent or regress atherosclerosis, whereas inhibition of P450 blocks oxidative reactions, promotes cholesterol accumulation, and enhances the atherosclerotic vascular process.
Assuntos
Aterosclerose/prevenção & controle , Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/fisiologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Aterosclerose/enzimologia , Colesterol/fisiologia , HDL-Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Proteínas de Ligação a DNA , Endotélio Vascular/metabolismo , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Bile duct ligation in male rats for two weeks led to a marked increase in both serum sorbitol dehydrogenase activity and serum bile acid concentration indicating cholestatic liver injury. Furthermore, a rise in the hepatic hydroxyproline level indicating collagen accumulation was observed. As a consequence of these alterations, the hepatic microsomal mixed-function oxidase system was impaired as evidenced by a decrease in cytochrome P-450 content and in the activities of NADPH-cytochrome c reductase and aminopyrine-demethylase. While the hepatic glutathione content remained unaffected, the cytosolic GSH S-transferase activity was clearly suppressed due to subchronic cholestasis.
Assuntos
Colestase/enzimologia , Glutationa Transferase/análise , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/análise , Animais , Glutationa/análise , Fígado/patologia , Masculino , Ratos , Ratos EndogâmicosRESUMO
Subchronic treatment of male rats with carbon tetrachloride (CCl4, twice weekly 0.2 ml/kg p.o.) and feeding a 5% alcohol solution instead of drinking water led to a nearly complete liver cirrhosis in all animals within 4 weeks. This was also documented by a three fold increase in hepatic total hydroxyproline content. Steatosis was quantified by enhanced liver triglyceride concentrations and acute necroses by increments of serum enzyme activities (GPT, SDH). Daily oral treatment with malotilate (100 mg/kg) totally prevented the development of liver cirrhosis, hepatic hydroxyproline accumulation and increases in serum enzyme activities induced by CCl4-alcohol. In cianidanol-treated rats (100 mg/kg p.o.) only portoseptal fibrosis was seen, however hydroxyproline and triglyceride accumulation as well as enhanced serum enzyme activities were not suppressed. D-penicillamine (300 mg/kg p.o.) and colchicine (50 micrograms/kg i.p.) failed to protect rats against CCl4-alcohol induced fibrosis, necrosis and steatosis in this model.