RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is described by too much hepatic fat deposition causing steatosis, which further develops into nonalcoholic steatohepatitis (NASH), defined by necroinflammation and fibrosis, progressing further to hepatic cirrhosis, hepatocellular carcinoma, and liver failure. NAFLD is linked to different aspects of the metabolic syndrome like obesity, insulin resistance, hypertension, and dyslipidemia, and its pathogenesis involves several elements including diet, obesity, disruption of lipid homeostasis, and a high buildup of triglycerides and other lipids in liver cells. It is therefore linked to an increase in the susceptibility to developing diabetes mellitus and cardiovascular diseases. Several interventions exist regarding its management, but the availability of natural sources through diet will be a benefit in dealing with the disorder due to the immensely growing dependence of the population worldwide on natural sources owing to their ability to treat the root cause of the disease. Anthocyanins (ACNs) are naturally occurring polyphenolic pigments that exist in the form of glycosides, which are the glucosides of anthocyanidins and are produced from flavonoids via the phenyl propanoid pathway. To understand their mode of action in NAFLD and their therapeutic potential, the literature on in vitro, in vivo, and clinical trials on naturally occurring ACN-rich sources was exhaustively reviewed. It was concluded that ACNs show their potential in the treatment of NAFLD through their antioxidant properties and their efficacy to control lipid metabolism, glucose homeostasis, transcription factors, and inflammation. This led to the conclusion that ACNs possess efficacy in the amelioration of NAFLD and the various features associated with it. However, additional clinical trials are required to justify the potential of ACNs in NAFLD.
Asunto(s)
Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Antocianinas/farmacología , Antocianinas/uso terapéutico , Antocianinas/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/patología , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Fitoquímicos/metabolismo , Hígado/metabolismo , Hígado/patologíaRESUMEN
OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but T2D screening tests are not well validated in this population. In this study, we assessed performance of glycated hemoglobin (A1C) and fasting plasma glucose (FPG) in glucose dysmetabolism screening and aimed to optimize detection thresholds for individuals with NAFLD. METHODS: We retrospectively included oral glucose tolerance tests (OGTTs) from consecutive patients undergoing a specialized clinic for NAFLD, if A1C and/or fasting glucose was available within 3 months of OGTT. We compared performances of A1C and fasting glucose with the "gold standard" of OGTT using thresholds from the 2018 Diabetes Canada guidelines. A1C and FPG thresholds were optimized for detection of glucose dysmetabolism using receiver operating characteristic curves. RESULTS: We included 63 OGTTs from individuals with NAFLD (52% female, age 48 [interquartile range 35 to 63] years, body mass index 34 [interquartile range 29 to 40] kg/m2). A1C had 16% (95% confidence interval [CI] 6% to 38%) sensitivity (Se) and 97% (95% CI 85% to 100%) specificity (Sp) for T2D detection, and 45% (95% CI 30% to 62%) Se and 100% (95% CI 83% to 100%) Sp for abnormal blood glucose detection. FPG had 67% (95% CI 45% to 83%) Se and 100% (95% CI 92% to 100%) Sp for T2D detection, and 74% (95% CI 59% to 85%) Se and 92% (95% CI 74% to 99%) Sp for abnormal blood glucose detection. Optimal A1C and FPG thresholds were 5.6% and 6.3 mmol/L for T2D detection, which are lower than current recommendations. CONCLUSIONS: A1C is less sensitive than FPG and is suboptimal for T2D detection, suggesting that OGTT may be obtained if A1C is ≥5.6% or FPG is ≥6.3 mmol/L in individuals with NAFLD, to avoid underdiagnosis and treatment inertia.
Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Enfermedad del Hígado Graso no Alcohólico , Estado Prediabético , Humanos , Adulto , Femenino , Persona de Mediana Edad , Masculino , Hemoglobina Glucada , Estado Prediabético/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Glucemia , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Estudios Retrospectivos , Glucosa , Ayuno , Diabetes Mellitus/epidemiologíaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) has been recently termed metabolic dysfunction-associated fatty liver disease (MAFLD) to address the strong association with the metabolic syndrome. The prevalence of MAFLD is significantly increased in obese individuals and treatment of obesity is currently the cornerstone of management of MAFLD. Bariatric and metabolic surgery nowadays emerges as a key therapeutic strategy for the treatment of the MAFLD. This review aims to provide an update on the novel studies reporting the outcomes of bariatric surgery on the spectrum of MAFLD, from hepatic steatosis to cirrhosis.
Asunto(s)
Cirugía Bariátrica , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/cirugía , Obesidad/complicaciones , Obesidad/cirugía , Síndrome Metabólico/complicaciones , Síndrome Metabólico/cirugíaRESUMEN
Context and objectives As the global epidemic of obesity and metabolic syndrome progresses, the coexistence of fatty liver disease in patients with chronic viral hepatitis B (VHB) becomes significant. The objective of this work was to determine the frequency of hepatic steatosis assessed by Fibroscan/CAP (Controlled Attenuation Parameter) in patients with chronic VHB in Côte d'Ivoire. Methods. The study included 83 patients with chronic VHB. These were black patients who had performed a Fibroscan/CAP during the recruitment period and were willing to participate in the study. Patients with significant alcohol consumption, a secondary cause of hepatic steatosis, another liver disease regardless of the etiology associated with VHB were not included. Results. The frequency of hepatic steatosis in chronic HBV carriers assessed by CAP in our study population was 48.19 %, including 24.10 % of severe steatosis. Obesity was statistically correlated with the presence of steatosis in our patients. Patients who had steatosis on ultrasound were 5 times more likely to have steatosis on CAP. Significant fibrosis was insignificantly associated with steatosis. Conclusion. The frequency of fatty liver disease detected by fibroscan/CAP is high in patients with chronic VHB.
Contexte et objectifs Avec la progression de l'épidémie mondiale d'obésité et du syndrome métabolique, la coexistence d'une stéatose hépatique chez les patients porteurs d'une hépatite virale B chronique devient non négligeable. L'objectif de ce travail était de déterminer la fréquence de la stéatose hépatique chez les patients porteurs d'une hépatite virale B (HVB) chronique. Méthodes. Il s'agissait d'une série des cas de HVB de race noire, ayant réalisé un Fibroscan/CAP pendant la période du recrutement et consentants à participer à l'étude. Les patients ayant une consommation d'alcool significative, une cause secondaire de stéatose hépatique, une autre hépatopathie quelle que soit l'étiologie associée à l'hépatite B n'ont pas été inclus. Résultats. Quatre-vingt-trois patients porteurs d'une HVB ont été inclus. La fréquence de la stéatose hépatique chez les porteurs du VHB chronique était de 48,19 % dont 24,10 % de stéatose sévère. L'obésité était statistiquement corrélée à la présence d'une stéatose chez nos patients. Les patients qui avaient une stéatose à l'échographie étaient 5 fois plus à risque d'avoir une stéatose au CAP. La fibrose significative était associée de façon non significative à la stéatose. Conclusion : Près de la moitié des patients porteurs d'une hépatite virale B chronique présente une stéatose hépatique.
Asunto(s)
Humanos , Masculino , Femenino , Hígado GrasoRESUMEN
Acute fatty liver of pregnancy (AFLP) is a specific but rare hepatopathy that can usually complicate the third trimester of pregnancy. It is potentially fatal for the mother and the fetus. To our knowledge, only eight cases of recurrence have been published, we report a new case. The first episode presented by our 23-year-old patient was suspected in front of a cutaneous-mucosal jaundice with vomiting occurring on pregnancy of 35weeks of gestation (WG). Hyperleucytosis, abnormalities of the hepatic balance, as well as a hypoglycemia were biological elements supporting the diagnostic beam. On the other hand, medical imaging could not bring a clear confirmation. The evolution was favorable after deferred delivery by caesarean section for pulmonary maturation. Three years later, she presented to the obstetrical emergency room at 36weeks and six days of gestation, with a clinical and biological picture almost similar to that of the first episode. A caesarean section was then indicated for suspicion of recurrence. The evolution is favorable for the mother and her children. The interest of the communication on the risk of recurrence, the clinical and biological monitoring in particular in the third trimester of the subsequent pregnancy are imperative, in order to improve the prognosis of this pathology.
Asunto(s)
Hígado Graso , Complicaciones del Embarazo , Adulto , Cesárea , Niño , Hígado Graso/complicaciones , Hígado Graso/diagnóstico , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/diagnóstico , Tercer Trimestre del Embarazo , Adulto JovenRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver in the absence of alcohol and increases one's risk for both diabetes and cardiovascular disease (e.g., angina). We have shown that the second-line anti-anginal therapy, ranolazine, mitigates obesity-induced NAFLD, and our aim was to determine whether these actions of ranolazine also extend to NAFLD associated with type 2 diabetes (T2D). Eight-week-old male C57BL/6J mice were fed either a low-fat diet or a high-fat diet for 15 weeks, with a single dose of streptozotocin (STZ; 75 mg/kg) administered in the high-fat diet-fed mice at 4 weeks to induce experimental T2D. Mice were treated with either vehicle control or ranolazine during the final 7 weeks (50 mg/kg once daily). We assessed glycemia via monitoring glucose tolerance, insulin tolerance, and pyruvate tolerance, whereas hepatic steatosis was assessed via quantifying triacylglycerol content. We observed that ranolazine did not improve glycemia in mice with experimental T2D, while also having no impact on hepatic triacylglycerol content. Therefore, the salutary actions of ranolazine against NAFLD may be limited to obese individuals but not those who are obese with T2D.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Animales , Glucemia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Ranolazina/farmacología , Ranolazina/uso terapéutico , Estreptozocina , TriglicéridosRESUMEN
Fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor antidepressant, has been shown to increase hepatic lipid accumulation, a key factor in the development of nonalcoholic fatty liver disease. Interestingly, fluoxetine has also been reported to increase peripheral serotonin synthesis. As emerging evidence suggests that serotonin may be involved in the development of nonalcoholic fatty liver disease, we sought to determine if fluoxetine-induced hepatic lipid accumulation is mediated via altered serotonin production. Fluoxetine treatment increased lipid accumulation in association with increased mRNA expression of tryptophan hydroxylase 1 (Tph1, serotonin biosynthetic enzyme) and intracellular serotonin content. Serotonin alone had a similar effect to increase lipid accumulation. Moreover, blocking serotonin synthesis reversed the fluoxetine-induced increases in lipid accumulation. Collectively, these data suggest that fluoxetine-induced lipid accumulation can be mediated, in part, by elevated serotonin production. These results suggest a potential therapeutic target to ameliorate the adverse metabolic effects of fluoxetine exposure.
Asunto(s)
Fluoxetina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Serotonina/biosíntesis , Línea Celular Tumoral , Humanos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triptófano Hidroxilasa/genéticaRESUMEN
Theobromine, a methylxanthine present in cocoa, has been shown to possess many beneficial pharmacological properties such as anti-oxidative stress, anti-inflammatory property, and anti-microbial activity. In this study, we investigated the effects of theobromine on nonalcoholic fatty liver disease (NAFLD) and the possible underlying mechanisms in vivo and in vitro. The results showed that theobromine reduced body weight and fat mass and improved dyslipidemia. Theobromine mitigated liver injury and significantly reduced hepatic triglyceride level in mice with obesity. Histological examinations also showed hepatic steatosis was alleviated after theobromine treatment. Furthermore, theobromine reversed the elevated mRNA and protein expression of SREBP-1c, FASN, CD36, FABP4, and the suppressed expression of PPARα and CPT1a in the liver of mice with obesity, which were responsible for lipogenesis, fatty acid uptake, and fatty acid oxidation respectively. In vitro, theobromine also downregulated SREBP-1c, FASN, CD36, FABP4 and upregulated PPARα and CPT1a mRNA and protein levels in hepatocytes in a dose-dependent manner, while these changes were reversed by L-leucine, a mammalian target of rapamycin (mTOR) agonist. The present study demonstrated that theobromine improved NAFLD by inhibiting lipogenesis and fatty acid uptake and promoting fatty acid oxidation in the liver and hepatocytes, which might be associated with its suppression of mTOR signaling pathway. Novelty: Theobromine protects against high-fat diet - induced NAFLD. Theobromine inhibits lipogenesis and fatty acid uptake and promotes fatty acid oxidation in the liver and hepatocytes via inhibiting mTOR signaling pathway.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Lipogénesis , Masculino , RatonesRESUMEN
The present study examined the effectiveness of adding exercises with whole-body vibration (WBV) to aerobic training in terms of metabolic features and quality of life. Patients with non-alcoholic fatty liver disease (NAFLD), confirmed on imaging, underwent an 8-week individualized exercise program randomized between aerobic training with and without WBV. Training was performed at 60-80% heart rate workload for 165 min/week. The WBV amplitude was 2-4mm and the training frequency was 30Hz, for 15min. Assessments were carried out on surrogate scores of steatosis and fibrosis including transient elastography (FibroScan), metabolic features (biochemical analysis) and quality of life (SF-36). Insulin resistance was markedly reduced (-2.36; 95% CI: -4.96 to -0.24; P: 0.049) in aerobic training with WBV. The decrease in serum aspartate transaminase was significantly greater in aerobic training without WBV (-14.81; 95% CI: -23.36 to -6.25; P: 0.029). There were no significant differences between groups for the other metabolic features (P<0.05). All quality of life well-being domains improved in both groups (P<0.05). Given this reduction in insulin resistance, WBV can usefully be added to aerobic training. However, WBV did not provide further benefits in improving metabolic properties or quality of life.
Asunto(s)
Terapia por Ejercicio/métodos , Enfermedad del Hígado Graso no Alcohólico/terapia , Acondicionamiento Físico Humano/métodos , Calidad de Vida , Vibración/uso terapéutico , Adulto , Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/psicología , Resultado del TratamientoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is an excessive accumulation of fats in the liver resulting in hepatic inflammation and fibrous tissue formation along with insulin resistance. This study was designed to investigate the possible protective effects of metformin alone and in combination with different phosphodiesterase inhibitors (PDEIs). Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Starting from week 12, rats received metformin alone or in combination with pentoxifylline, cilostazol, or sildenafil. HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, significant elevations were recorded compared to control in terms of serum glucose, insulin, and HOMA-IR (homeostasis model assessment index for insulin resistance), oxidative stress parameters, hepatic TNF-α and NF-κB gene expression, and iNOS protein expression. Rats treated with metformin showed a significant improvement in the aforementioned parameters. However, the addition of pentoxifylline to metformin treatment synergized its action and produced a fortified effect against HFD-induced NAFLD better than other PDEIs. Data from this study indicated that combined treatment of metformin and pentoxifylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are needed to approve PDEIs for NAFLD treatment.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Metformina/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Glucemia/metabolismo , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Sinergismo Farmacológico , Ayuno/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Malondialdehído/metabolismo , Metformina/uso terapéutico , FN-kappa B/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Inhibidores de Fosfodiesterasa/uso terapéutico , Ratas , Ratas Wistar , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
INTRODUCTION: Obstructive sleep apnoea (OSA) is commonly associated with non-alcoholic fatty liver disease (NAFLD). Early identification of NAFLD in OSA patients is important in order to try to prevent its evolution to advanced stages. The objective of this study was to determine the prevalence and risk factors for the occurrence of NAFLD in OSA patients. METHOD: A cross-sectional analysis including 124 OSA patients examined in the pulmonology department of Abderahmane Mami Hospital between January 2017 and March 2018 was undertaken. NAFLD was diagnosed using an abdominal ultrasonography. Data were analysed in a univariate and multivariate fashion in order to determine the characteristics of OSA patients with and without NAFLD. RESULTS: NAFLD was found in 62.9 % patients, with a frequency according to OSA severity of 51.3 %, 56.5 % and 72.6 % in mild, moderate and severe OSA, respectively. Severe OSA multiplies by 2.32 the risk of having NAFLD. The comparison between groups with and without NAFLD reveals that patients with the disease were younger, more obese, had more severe OSA, lower nocturnal oxygen saturation during sleep, and higher ALAT levels. Multivariate analysis showed a statistically significant link between NAFLD and serum ALAT elevation and the oxygen desaturation index. CONCLUSIONS: NAFLD is a frequent comorbidity in OSA, correlated to the severity of the disease. Thus, early screening of the disease in OSA patients especially in younger obese patients with high ALAT serum levels and a high oxygen desaturation index is proposed.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/etiología , Prevalencia , Factores de Riesgo , Apnea Obstructiva del Sueño/etiología , Túnez/epidemiología , Adulto JovenRESUMEN
Post-transplantation nonalcoholic fatty liver disease (NAFLD) is common in liver transplant recipients. Changes in the expression levels and activities of drug-metabolizing enzymes and drug transporters have been reported in patients with NAFLD and relevant rodent models. Here, we evaluated whether the pharmacokinetics of mycophenolic acid (MPA), an immunosuppressant, would be altered in rats with NAFLD. NAFLD was induced by feeding a diet containing 1% (w/w) orotic acid for 20 days. The extent of hepatic glucuronidation of MPA to a major metabolite, mycophenolic acid-7-O-glucuronide (MPAG), did not differ between rats with NAFLD and controls. The expression levels of hepatic multidrug resistance-associated protein 2, responsible for biliary excretion of MPAG, were comparable in rats with NAFLD and controls; the biliary excretion of MPAG was also similar in the two groups. Compared with control rats, rats with NAFLD did not exhibit significant changes in the areas under the plasma concentration - time curves of MPA or MPAG after intravenous (5 mg/kg) or oral (10 mg/kg) administration of MPA. However, delayed oral absorption of MPA was observed in rats with NAFLD compared with controls; the MPA and MPAG peak plasma concentrations fell significantly and the times to achieve them were prolonged following oral administration of MPA.
Asunto(s)
Glucurónidos/farmacocinética , Microsomas Hepáticos/metabolismo , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Enfermedad del Hígado Graso no Alcohólico/patología , Ácido Orótico/toxicidad , Animales , Masculino , Ácido Micofenólico/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Resveratrol (RSV), a well-known bioactive compound, has been reported to exert a broad range of health benefits. Accumulating evidence suggests that RSV is beneficial for many metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). This study investigated the preventive and therapeutic effects of RSV on high-fat diet (HFD)-induced NAFLD in rats and palmitate acid (PA)-induced hepatocyte steatosis in HepG2 cells. Hepatocytes were incubated with inhibitors of peroxisome proliferator-activated receptor α (PPARα) or short interfering RNAs (siRNAs) targeting PPARα, AMP-activated protein kinase (AMPK), and protein kinase A (PKA) to determine the underlying mechanisms. We found that RSV noticeably ameliorated HFD-induced hepatic steatosis in rats and inhibited PA-induced lipid accumulation in HepG2 cells. Moreover, RSV improved lipid metabolism, enhanced antioxidant capacity, and restored mitochondrial respiratory chain activities. Incubation with inhibitors of PPARα or PPARα siRNA abolished the protective effects of RSV on lipid metabolism and redox homeostasis. Furthermore, RSV activated the PKA/AMPK/PPARα signaling pathway. Our results provided direct evidence for a novel, PPARα-mediated mechanism responsible for the beneficial effects of RSV on hepatic steatosis. These findings may have important theoretical and application prospects for the prevention and treatment of NAFLD. Novelty RSV improved lipid metabolism and redox homeostasis and oxidative stress in NAFLD via the PKA/AMPK/PPARα signaling pathway. RSV may have a greater beneficial effect in the early prevention of hepatic steatosis.
Asunto(s)
Antioxidantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , PPAR alfa/metabolismo , Resveratrol/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Homeostasis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oxidación-Reducción , PPAR alfa/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Fructose contributes to the development of nonalcoholic fatty liver disease (NAFLD). ß-Sitosterol (Bst), a naturally occurring phytosterol, has antihyperlipidaemic and hepatoprotective properties. This study interrogated the potential protective effect of ß-sitosterol against NAFLD in growing rats fed a high-fructose diet, modelling children fed obesogenic diets. Forty-four 21 day old male rat pups were randomly allocated to and administered the following treatments for 12 weeks: group I, standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group II, SRC + 20% w/v fructose solution (FS) as drinking fluid + PC; group III, SRC + FS + 100 mg/kg fenofibrate in a gelatine cube; group IV, SRC + FS + 20 mg/kg ß-sitosterol gelatine cube (Bst); group V, SRC + PW + Bst. Terminally, the livers were dissected out, weighed, total liver lipid content determined, and histological analyses done. Harvested plasma was used to determine the surrogate biomarkers of liver function. The high-fructose diet caused increased (p < 0.05) hepatic lipid (total) accretion (>10% liver mass), micro- and macrovesicular hepatic steatosis, and hepatic inflammation. ß-Sitosterol and fenofibrate prevented the high-fructose diet-induced macrovesicular steatosis and prevented the progression of NAFLD to steatohepatitis. ß-Sitosterol can prospectively be used to mitigate diet-induced NAFLD.
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Fructosa/efectos adversos , Hipolipemiantes/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Sitoesteroles/farmacología , Animales , Dieta/efectos adversos , Lípidos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Perilipin 5 (Plin5), a member of the PAT (Perilipin, ADRP, and Tip47) protein family, has been implicated in the regulation of cellular neutral lipid accumulation in nonalcoholic fatty liver diseases. However, the underlying regulatory mechanisms of Plin5 are not clear. The goal of the present study was to explore the mechanism of oleic acid (OA)-induced Plin5 expression in HepG2 cells. We found that the expression of Plin5 was increased during OA-induced lipid droplets formation in a dose- and time-dependent manner. During this process of OA-stimulated lipid droplets formation, peroxisome proliferator-activated receptor alpha (PPARα) was also upregulated. When PPARα activation was blocked by GW6471, OA-induced Plin5 expression and lipid droplets formation were effectively ablated. We further found that the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was able to downregulate both PPARα and Plin5 expression and lipid droplets formation. Thus, we concluded that PI3K may, at least in part, act upstream of PPARα to regulate Plin5 expression and lipid droplets formation in HepG2 cells.
Asunto(s)
Gotas Lipídicas/fisiología , Ácido Oléico/farmacología , PPAR alfa/metabolismo , Perilipina-5/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Compuestos Azo/química , Cromonas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Imidazoles/farmacología , Morfolinas/farmacología , Oxazoles/farmacología , PPAR alfa/antagonistas & inhibidores , PPAR alfa/genética , Perilipina-5/genética , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Piridinas/farmacología , Coloración y Etiquetado , Sulfonas/farmacología , Tiofenos/farmacología , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
ARHGAP21 is a Rho-GAP that controls GTPases activity in several tissues, but its role on liver lipid metabolism is unknown. Thus, to achieve the Rho-GAP role in the liver, control and ARHGAP21-haplodeficient mice were fed chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD) for 12 weeks, and pyruvate and insulin tolerance tests, insulin signaling, liver glycogen and triglycerides content, gene and protein expression, and very-low-density lipoprotein secretion were measured. Het mice displayed reduced body weight and plasma triglycerides levels, and increased liver insulin signaling. Reduced gluconeogenesis and increased glycogen content were observed in Het-HFD mice. Gene and protein expression of microsomal triglyceride transfer protein were reduced in both Het mice, while the lipogenic genes SREBP-1c and ACC were increased. ARHGAP21 knockdown resulted in hepatic steatosis through increased hepatic lipogenesis activity coupled with decreases in CPT1a expression and very-low-density lipoprotein export. In conclusion, liver of ARHGAP21-haplodeficient mice are more insulin sensitive, associated with higher lipid synthesis and lower lipid export.
Asunto(s)
Proteínas Activadoras de GTPasa/deficiencia , Técnicas de Inactivación de Genes , Insulina/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Obesidad/metabolismo , Obesidad/patología , Animales , Proteínas Activadoras de GTPasa/genética , Glucosa/biosíntesis , Glucógeno/metabolismo , Metabolismo de los Lípidos/genética , Lipoproteínas VLDL/biosíntesis , Lipoproteínas VLDL/metabolismo , Hígado/patología , Ratones , Transducción de Señal/genéticaRESUMEN
This study investigated the effects of curcumin and capsaicin on testicular and hepatic oxidant-antioxidant status in rats fed a high-fat diet (HFD). Male Sprague-Dawley rats were divided into 5 groups (8 rats per group). The control group was fed a normal control diet (standard laboratory chow), the HFD group was fed HFD (60% of total calories from fat), the HFD+CUR group received HFD supplemented with curcumin (1.5 g curcumin/kg HFD), the HFD+CAP group was given HFD supplemented with capsaicin (0.15 g capsaicin/kg HFD), and the HFD+CUR+CAP group received HFD supplemented with curcumin and capsaicin for 16 weeks. Hepatic and testicular thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS), glutathione (GSH) levels, glutathione transferase activity, and Cu-Zn superoxide dismutase, glutathione peroxidase, and catalase protein expression and enzyme activities were measured. Protein expression was determined by Western blotting. GSH levels and antioxidant enzyme activities were measured with colorimetric methods. HFD slightly increased hepatic and testicular oxidative stress parameters. GSH levels did not change between groups. TBARS and ROS levels were significantly reduced in the HFD+CUR+CAP group compared with the HFD group. Liver and testis antioxidant enzyme activities and expression increased significantly with combined capsaicin and curcumin treatment. Curcumin and capsaicin treatment attenuated testicular and hepatic oxidative stress and enhanced the antioxidant defense system. The combination of capsaicin and curcumin with HFD seems to have some remarkable and beneficial effects on testicular oxidative damage in the fatty liver rat model.
Asunto(s)
Antioxidantes/metabolismo , Capsaicina/farmacología , Curcumina/farmacología , Dieta Alta en Grasa , Dieta , Hígado/efectos de los fármacos , Hígado/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Animales , Hígado Graso/metabolismo , Glutatión/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
In high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD), there is an increase in the endocannabinoid system activity, which significantly contributes to steatosis development. The aim of our study was to investigate the effects of cannabinoid receptor type 1 blockade on adipokine and proinflammatory cytokine content in adipose and hepatic tissue in mice with NAFLD. Male mice C57BL/6 were divided into a control group fed with a control diet for 20 weeks (C, n = 6) a group fed with a HFD for 20 weeks (HF, n = 6), a group fed with a control diet and treated with rimonabant after 18 weeks (R, n = 9), and a group fed with HFD and treated with rimonabant after 18 weeks (HFR, n = 10). Rimonabant significantly decreased leptin, resistin, apelin, visfatin, interleukin 6 (IL-6), and interferon-γ (IFN-γ) concentration in subcutaneous and visceral adipose tissue in the HFR group compared to the HF group (p < 0.01). Rimonabant reduced hepatic IL-6 and IFN-γ concentration as well as plasma glucose and insulin concentration and the homeostatic model assessment index in the HFR group compared to the HF group (p < 0.01). It can be concluded that the potential usefulness of CB1 blockade in the treatment of HFD-induced NAFLD is due to modulation of the adipokine profile and proinflammatory cytokines in both adipose tissues and liver as well as glucose metabolism.
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Antagonistas de Receptores de Cannabinoides/farmacología , Citocinas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptor Cannabinoide CB1/antagonistas & inhibidores , Rimonabant/farmacología , Adipoquinas/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/efectos de los fármacos , Antagonistas de Receptores de Cannabinoides/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Glucosa/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Rimonabant/uso terapéuticoRESUMEN
OBJECTIVES: It is unclear whether liver enzymes or the interactions of various liver enzymes is a predictor of type 2 diabetes mellitus (T2DM), which is independent of fatty liver. METHODS: A total of 48,001 subjects participated in baseline examinations. Among the subjects, 33,355 were followed for an average of 2.2 years. Cox proportional hazard models were used to examine the adjusted associations of AST, GGT and ALT with T2DM. RESULTS: The cumulative incidence of T2DM was 8.05% to 9.02% for fatty liver and 2.25% to 4.10% for non-fatty liver, both showing statistically significant differences. Compared with the normal liver enzyme levels in the group with fatty liver, the adjusted incident hazard ratios in T2DM were: ALT 1.23 (95% CI 1.10 to 1.50); AST 1.30 (95% CI 1.07-1.59); and GGT 1.34 (95% CI 1.08 to 1.65). In addition, compared with the normal liver enzyme levels in the group with non-fatty liver, the adjusted incident hazard ratios in type 2 diabetes were: ALT 1.27 (95% CI 1.02 to 1.59); AST 1.33 (95% CI 1.02 to 1.59); and GGT 1.53 (95% CI 1.19 to 1.98). There are significant interactions of T2DM hazard ratios between GGT and ALT and between GGT and AST in addition to ALT and AST. CONCLUSIONS: Our results suggest that the incidence of T2DM in the group with fatty liver is significantly higher than that in the normal population, and the rise of serum AST, GGT and ALT levels are risk factors independent of fatty liver for the development of T2DM after adjusting for confounding factors.
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Diabetes Mellitus Tipo 2/enzimología , Hígado Graso/enzimología , Hígado/enzimología , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , China/epidemiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Hígado Graso/epidemiología , Femenino , Glutamil Aminopeptidasa/sangre , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores SocioeconómicosRESUMEN
Diabetes is one of the leading diseases worldwide and, thus, finding new therapeutic alternatives is essential. The development of non-alcoholic fatty liver disease is a notable diabetic complication. Therefore, antioxidant therapy became a leading topic in the world of diabetes research. The objective of this present study was to evaluate the effects of antioxidant N-acetylcysteine (NAC) administration on serum biochemical parameters and oxidative stress parameters in hepatic tissue of the diabetic rats. Thirty-two animals were divided in 4 groups (n = 8): G1, normal rats; G2, normal rats + NAC; G3, diabetic rats; and G4, diabetic rats + NAC. Diabetes was induced in diabetic groups through streptozotocin. NAC administration was effective in improving hyperglycemia and hypoinsulinemia, as well as reducing serum alanine-aminotransferase and urea, hepatic triglycerides accumulation, and oxidative stress biomarkers in the diabetic liver, as well as improving the activity of hepatic antioxidant enzymes. This effect was likely due to NAC's ability of restoring intracellular glutathione, an important compound for the antioxidant defense, as well as due to NAC's direct antioxidant properties. Thus, NAC administration was useful for reducing hepatic oxidative stress and decreased the deposit of triacylglycerols, minimizing diabetic hepatic damage, making it a promising therapeutic adjuvant in the future.