RESUMEN
INTRODUCTION: Telomeres may be considered markers of biological aging, shorter telomere length is associated with some age-related diseases; in several studies short telomere length has also been associated to obesity in adults and adolescents. However the relationship between telomere complex functions and obesity is still not clear. Aim of the study was to assess telomere length (TL) in adults' obese subjects before and after weight loss obtained by placement of bioenteric intragastric balloon (BIB) for 6months. METHODS: We enrolled 42 obese subjects before and after BIB placement as weight loss intervention. Blood samples were collected in order to obtain DNA from leukocyte to measure TL by quantitative PCR. RESULTS: Data were analyzed only in 37 subjects with complete data; all presented important body weight loss (124.06±26.7 vs 105.40±23.14, p<0.001) and more interesting they presented a significant increase in TL (3.58±0.83 vs 5.61±3.29, p<0.001). Moreover we observed a significant positive correlation between TL elongation and weight loss (r=0.44, p=0.007) as well as an inverse correlation between TL at baseline and TL elongation (r=-0.35, p=0.03).The predictors of TL elongation were once again weight loss and short TL at baseline (respectively p=0.007 and p=0.003). CONCLUSIONS: Our study shows that weight loss is associated to telomere lengthening in a positive correlation: the greater weight loss the greater telomere lengthening; moreover telomere lengthening is more significant in those subjects with shortest telomeres at baseline.
Asunto(s)
Obesidad/genética , Obesidad/terapia , Homeostasis del Telómero , Telómero/genética , Pérdida de Peso/genética , Adolescente , Adulto , Envejecimiento/genética , Femenino , Balón Gástrico , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
BACKGROUND AND AIMS: The first step in the alternative pathway of bile acid biosynthesis is the 27-hydroxylation of cholesterol, which takes place both in liver and extrahepatic tissues. This pathway is believed to play a role in peripheral cholesterol degradation. Aim of this study was to investigate the impact of hyperlipidemia on 27-hydroxycholesterol appearance rate, and to assess the effects induced by treatment with statins. METHODS AND RESULTS: Seven patients with familial hypercholesterolemia and eight patients with familial combined hyperlipidemia underwent determination of 27-hydroxylation rates in vivo by i.v. infusion of deuterated 27-hydroxycholesterol. Isotope enrichment was assayed by gas chromatography-mass spectrometry, allowing to calculate 27-hydroxycholesterol appearance rates. Six normocholesterolemic subjects were regarded as controls. In some hypercholesterolemic patients the infusions were repeated during treatment with atorvastatin or rosuvastatin. Hydroxylation rates were higher in hypercholesterolemic patients (8.7 ± 2.5 mg/h; controls, 3.4 ± 2.0 mg/h; combined hyperlipidemia, 4.4 ± 1.6 mg/h; mean ± SD, P < 0.01 vs both). After statin treatment, both plasma cholesterol levels and hydroxylation rates dropped by nearly 50%. No difference was detectable between the two statins. A linear correlation was shown between plasma cholesterol and 27-hydroxylation rates. CONCLUSION: Hypercholesterolemia associates with increased 27-hydroxycholesterol appearance rates, which decrease during hypocholesterolemic treatment. The correlation with cholesterol levels supports the view that 27-hydroxylation may act as a compensatory mechanism in a condition of larger plasma cholesterol pool. A regulatory role for hepatic and extrahepatic nuclear receptors seems reasonable. These data prompt novel pharmacological approaches for the management of hypercholesterolemia and the prevention of atherosclerosis.
Asunto(s)
Hidroxicolesteroles/sangre , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Adulto , Anciano , Anticolesterolemiantes/uso terapéutico , Atorvastatina , Estudios de Casos y Controles , Colesterol/sangre , Colesterol/metabolismo , Femenino , Fluorobencenos/uso terapéutico , Cromatografía de Gases y Espectrometría de Masas , Ácidos Heptanoicos/uso terapéutico , Humanos , Hidroxilación , Hipercolesterolemia/fisiopatología , Hiperlipidemia Familiar Combinada/tratamiento farmacológico , Hiperlipidemia Familiar Combinada/fisiopatología , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/fisiopatología , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Rosuvastatina Cálcica , Sulfonamidas/uso terapéuticoRESUMEN
The liver plays a central role in the regulation of cholesterol homeostasis. Hepatic cholesterol content is maintained by a complex interplay between input and output pathways; alterations in the balance among these processes may lead to accumulation of excess cholesterol in body compartments with potentially deleterious consequences at the level of blood vessels (atherosclerosis) and biliary tract (gallstone disease). Molecular biology has brought new insights into this field. Nuclear receptors have been shown to play a key role in the "sensing" of intracellular cholesterol levels and in the triggering of metabolic responses via the sterol regulatory element binding protein (SREBP) cascade. A nuclear receptor for bile acids, farnesoid X receptor (FXR), has been identified and the molecular pathways underlying feedback inhibition of bile acid synthesis, the main mechanism of irreversible degradation of cholesterol, have been clarified. Such regulation involves a number of additional coactivators/corepressors of the transcription of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase. Finally, the main transporters of biliary lipids (bile acids, phospholipids and cholesterol) have been described; most of them undergo transcriptional control by nuclear receptors, allowing regulation of biliary lipid efflux in conditions of different intracellular availability. Despite a body of evidence coming from experimental models the intimate mechanisms of regulation have not been clearly defined and direct evidence in humans is rather limited. This review will focus on the role of nuclear receptors in the regulation of hepatic cholesterol degradation and biliary lipid secretion, and on the theoretical applications from a pharmacotherapeutic perspective.
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Colesterol/metabolismo , Cálculos Biliares/metabolismo , Hígado/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Ácidos y Sales Biliares/biosíntesis , Ácidos y Sales Biliares/metabolismo , Humanos , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
BACKGROUND: Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers. DESIGN: Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry. RESULTS: Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed. CONCLUSIONS: Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism.
Asunto(s)
Envejecimiento/metabolismo , Ácidos y Sales Biliares/biosíntesis , Colesterol 7-alfa-Hidroxilasa/metabolismo , Factor Nuclear 4 del Hepatocito/genética , Hígado/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Factor Nuclear 4 del Hepatocito/análisis , Humanos , Lipogénesis , Masculino , Persona de Mediana Edad , Receptores Citoplasmáticos y NuclearesRESUMEN
BACKGROUND: Cholesterol cholelithiasis (gallstone disease) is a common disease in the Western world. The aim of the present study was to analyze the hepatic expression of a number of nuclear receptors involved in bile acid metabolism in human cholesterol gallstone disease. MATERIALS AND METHODS: Surgical liver biopsies were obtained from 11 patients with untreated cholesterol cholelithiasis and nine gallstone-free subjects; mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1) and related nuclear receptors and coactivators were assayed by quantitative real-time RT-PCR. RESULTS: No differences between the two groups were detected in mRNA levels of CYP7A1 and related nuclear receptors, with the exception of peroxysome proliferator-activated receptor-gamma coactivator 1 (PGC-1), which was significantly (P < 0.01) less expressed in gallstone subjects. Expression of PGC-1 was linearly correlated with farnesoid X receptor (FXR) in gallstone patients (r = 0.87 on a log scale, P < 0.01), but not in control subjects; in gallstone patients PGC-1 expression was also correlated with hepatocyte nuclear factor 4 (HNF-4) (r = 0.78, P < 0.01). CONCLUSION: These findings suggest that PGC-1 can play a role in the prevention of cholesterol gallstone disease in humans; this might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models and other coactivators. The present data might help to understand the pathophysiology and possibly focus on new therapeutical targets in cholesterol gallstone disease.
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Colelitiasis/metabolismo , Hígado/química , Factores de Transcripción/análisis , Ácidos y Sales Biliares/biosíntesis , Biomarcadores/sangre , Colestenonas/sangre , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilasa/análisis , Colesterol 7-alfa-Hidroxilasa/genética , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Femenino , Regulación de la Expresión Génica/genética , Factor Nuclear 4 del Hepatocito/análisis , Factor Nuclear 4 del Hepatocito/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Receptores Citoplasmáticos y Nucleares , Factores de Transcripción/genéticaRESUMEN
Hyperlipidaemia represents a determinant for the development of atherosclerosis and an important risk factor for cardiovascular disease, particularly in the context of the insulin resistance syndrome. This is characterized by alterations in the profile of plasma lipoprotein including high triglyceride levels, low high-density lipoprotein cholesterol concentrations and the appearance of qualitatively modified, small-dense low-density lipoproteins. Many charts and algorithms have been developed to estimate the entity of coronary and cardiovascular risk as related to dyslipidaemia, on the basis of additional individual risk factors and conditions: most include age and gender, smoking status, hypertension and diabetes. They should preferably be utilized in consistent patient populations, in terms of geographical areas and general risk profile. Pharmacological treatment of dyslipidaemia, in particular with statin drugs, was shown to greatly improve cardiovascular morbidity and mortality. A body of evidence also underlines the need for a multidisciplinary approach, integrating non-pharmacological lifestyle and diet interventions, as well as treatment of concomitant diseases (hypertension and diabetes).
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Enfermedades Cardiovasculares/etiología , Hiperlipidemias/complicaciones , Aterosclerosis/etiología , Complicaciones de la Diabetes/etiología , Humanos , Hiperlipidemias/tratamiento farmacológico , Grupo de Atención al Paciente , Factores de RiesgoRESUMEN
The Baker's cyst is a distension of the bursa subtendinea and is caused by noninfectious knee effusion secondary to arthrosis, meniscal tears, trauma, rheumatoid arthritis, gout, or any other form of sinovitis, like rheumatoid arthritis. An infected popliteal cyst is much less common; tuberculous arthritis is exceptional, in fact only four cases are described in literature. Herein we describe an additional tbc case of a 51 years old men, who has been initially treated with cytostatic and corticosteroid agents, for a suspected rheumatoid arthritis. The review of the literature suggests the importance of a correct approach to the diagnosis, based on the analysis and culture of the synovial fluid, because delays latency of effective antibiotic therapy can result in permanent joint damage that invalidate the patients.