Effect of diet/atorvastatin on atherosclerotic lesions associated to nonalcoholic fatty liver disease in chickens.

Comparative histological examination of both liver and the supra-aortic arteries have not previously examined the consequences of atherosclerosis and nonalcoholic fatty liver disease (NAFLD), and their response to diet and atorvastatin therapy. This study evaluates the effects of diet alone or in combination with atorvastatin therapy on the progression/regression of atherosclerosis and its correlation with NAFLD. This research was performed on a cohort of chickens on standard (SD) or hyperlipidemic diets (HD), either with or without atorvastatin therapy. The development of atherosclerotic lesions was assessed by histology, immunohistochemistry and quantitative image analysis and correlated with liver histology. The lowest levels of atherosclerotic lesions were found in animals on the HD for 3 months, followed by 3 months of SD in combination with oral atorvastatin. There was a strong association between the histologic findings of atherosclerosis and those of NAFLD. These studies show that standard diet and atorvastatin therapy can positively affect both arterial and hepatic lesions, influencing the regression of the changes. These results support the hypothesis that NAFLD and atherosclerosis may be actually two aspects of a shared disease and suggest the possibility of regression of both disorders with dietary and pharmacologic manipulations.

Effect of atorvastatin and diet on non-alcoholic fatty liver disease activity score in hyperlipidemic chickens.

Non-alcoholic steatohepatitis (NASH) is part of the spectrum of non-alcoholic fatty liver disease (NAFLD), which includes from simple steatosis and steatohepatitis, to the most severe cirrhosis and carcinoma, which develops in the absence of excessive alcohol intake. NAFLD is the most common liver disorder in affluent societies. There is no proven treatment for NAFLD/NASH. One of the most frequent adverse effects of statins is an increase in hepatic aminotransferases. Studies that evaluate if the benefits of statins overcome the risks in NASH are lacking. The present study was conceived to explore the effect of both atorvastatin and diet on regression of steatohepatitis, using a chicken experimental model induced by a hyperlipidemic diet (HD). Plasma lipid levels, liver enzymes and hepatic histopathology, as well as image analysis were performed to determine changes in liver lipid deposits and inflammatory infiltration. Features of steatosis, cell-ballooning, and inflammation were scored to obtain the NAFLD activity score (NAS). A severe level of steatosis was found in animals fed on HD. Atorvastatin treated groups showed smaller size of lipid deposits and a lower level of inflammation than non-treated groups. Atorvastatin therapy induced a significant reduction of hepatocellular damage, even though in the animals which continuously received a hyperlipidemic diet. The combination of atorvastatin therapy and a standard diet produced the lowest decrease of NAS. Our results show that atorvastatin therapy not only decreased plasmatic levels of cholesterol and triglycerides, but also induced a reduction of liver steatosis, inflammation and hepatocellular damage, without increasing plasmatic aminotransferase levels.

Hyperlipidemic chicken as a model of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is part of the spectrum of non-alcoholic fatty liver disease (NAFLD), currently the most common cause of abnormal liver tests. Given the difficulty of studying all the factors involved in it in human populations, studies in animal models might provide crucial insights in the pathogenesis of steatohepatitis. Several physiological features predispose birds to fat deposition in the liver. The present study was conceived to explore the possibilities of the chicken fed a cholesterol and fat enriched diet as a model for steatohepatitis. We used two different diets: a standard growing mash (control group) and a standard growing mash enriched with 2% cholesterol and 20% palm oil (hyperlipidemic group). We investigated the effect of feeding a cholesterol and fat enriched diet, on plasma lipid levels, liver enzymes and hepatic histopathology. Semiquantitative and quantitative assessment by image analysis was performed to determine changes in lipid deposits and inflammatory infiltration. Statistically significant increases were observed in all plasma lipid parameters, liver macroscopic features, fat deposits and cell-ballooning of hepatocytes between control and hyperlipidemic animals. Significant differences were also observed in the inflammatory infiltration parameters (number of foci, density, area and maximal diameter). Results show that diet-induced hypercholesterolemia and hypertriglyceridemia are associated with severe impairment of liver histology (fat accumulation, inflammation and cell-ballooning), reproducing histological features of human NAFLD. This model, which is easy and reproducible, offers economic and technical advantages. Furthermore, the reversibility of the pathologic changes makes it suitable for drug intervention studies of steatohepatitis.

Efecto de la atorvastatina sobre la progresión y regresión de los depósitos grasos renales en un modelo experimental / Effect of atorvastatin on progression/regression of renal lipid accumulation in an experimental model

Introducción. Hay evidencias de la relación entre la arteriosclerosis y la enfermedad renal progresiva. Sin embargo, son escasos los estudios en humanos o animales en que se utilicen estatinas para valorar sus efectos sobre la lesión renal. Objetivos. El objetivo de este trabajo es estudiar a escala histológica el efecto de la atorvastatina sobre los fenómenos de progresión y regresión de los depósitos grasos en el riñón en un modelo experimental. Material y método. Para la realización de los protocolos experimentales se utilizaron 100 pollos White-Leghorn, sometidos a una dieta hiperlipémica en la fase de inducción y a diversos protocolos de dieta normal/dieta hiperlipémica y tratamiento o no con atorvastatina en la fase de intervención. Se realizó la valoración de la grasa renal mediante técnicas histológicas y análisis de imagen. Resultados. En el grupo control sano no se observó la existencia de depósitos grasos, mientras que el grupo aterogénico presentó grandes depósitos grasos. El grupo de regresión e intervención con atorvastatina presentó una menor presencia de grasa, lo que supuso una diferencia significativa con todos los grupos. También en el caso de este grupo, se encontró que el diámetro de la acumulación grasa es significativamente menor respecto al resto de los grupos. Conclusiones. Nuestro modelo experimental es, para el estudio del riñón graso, un modelo homogéneo y de fácil manejo. La retirada de la dieta grasa y la administración simultánea de atorvastatina da lugar a los índices más bajos de depósitos grasos renales. La retirada por sí sola de la dieta no produce efectos tan marcados. Del estudio de diferentes parámetros se deduce que la atorvastatina acelera la regresión y frena la progresión de las acumulaciones grasas renales (AU)

Introduction. There is evidence of a relationship between atherosclerosis and progressive kidney disease. However, information on the role of statins on kidney disease in humans and animal models is lacking. Objectives. To analyze the effect of atorvastatin on progression/regression of renal lipid accumulation in an experimental model using histological analysis. Material and method. We used 100 White-Leghorn chickens fed with a hyperlipemic diet (induction stage), followed by an interventional stage, in which the animals were fed a normal or hyperlipemic diet and administered atorvastatin or placebo. Assessment of renal lipid accumulation was made by histologic and imaging analyses. Results. In the healthy control group, no intracellular renal fat deposits or accumulations were found. The atherogenic group showed substantial lipid accumulations. The intervention group with suspension of the hyperlipemic diet and atorvastatin administration showed significant differences with the remaining groups, presenting the lowest fat accumulation. This group also showed significantly lower fat accumulation diameter with respect to the remaining groups. Conclusions. Our experimental model was useful and suitable for the study of renal fat accumulation. Hyperlipemic diet suspension and simultaneous atorvastatin therapy led to the lowest renal fat accumulation. Hyperlipemic diet suspension alone produced less pronounced results. The parameters studied indicate that atorvastatin was effective in accelerating regression of renal fat accumulation and in decreasing its progression (AU)