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Histomorphometric and metabolic liver changes in female Lewis rats depending on the diet and retinoic acid application

Introduction: High fat diet and related metabolic syndrome (MS) contribute to the development of liver steatosis, steatohepatitis and progressive fibrosis in animal and human model, leading to non- alcoholic fatty liver disease (NAFLD). NAFLD is characterized by accumulation of fatty droplets, different stages of fibronecrosis and is considered hepatic manifestation of metabolic syndrome. The prevalence of NAFLD is higher in obese individuals compared to general population. About 20% of patients with NAFLD develop non alcoholic steatohepatitis (NASH), a disorder that leads to other hepatic complications, such as portal hypertension, cirrhosis and hepatocellular carcinoma. Inflammatory cytokines, especially IL 1β and IL 18 as well as Toll like receptors have an important role in progression of NAFLD to NASH in animals. Retinoic acid (RA) ameliorates obesity and its related disorders, diminishing visceral fat depots and retroperitoneal white adipose tissue. On the other hand, due to an increased hepatic production of very low density lipoproteins (VLDL) and decreased lipoprotein lipase activity (LPL), its supplements cause hypertriglyceridaemia and dyslipidaemia, affecting atherogenic indicators. The aim of this study was to determine the effect of high fat diet and 13¬ cis retinoic acid (13 cRA) application on histological morphology of the liver (steatosis and fibrosis) and adipogenic and inflammatory indicators in female Lewis rats. Methods: The analysis included 36 Lewis rats bred at Department of Animal Physiology Zagreb. Half of the animals were fed high fat diet (HFD, 45% of saturated fatty acids) and half standard laboratory diet (STD) during 30 days. The groups were divided into additional 3 groups (6 rats each): two experimental groups that received 13 cRA orally on a daily basis during 30 days (7, 5 mg/kg and 15 mg/kg, respectively) and the control group was given distilled water. Animals were sacrificed after 60 days and serum for inflammatory cytokines and adipogenic indicators was taken, as well as liver for histological analysis. Results: 13 cRA and HFD caused dose-dependent microvesicular and macrovesicular steatosis in liver of experimental groups. An increase in atherogenic index, atherogenic ratio and cardiac risk was seen among experimental groups compared to the controls. Cardioprotective index was higher in control group. Fibrosis was not observed regardless of diet and 13-cRA treatment, which is probably because longer time is needed for pathological changes in liver, as well as its strong reparatory potential. Conclusion: 13 cRA and HFD affect atherogenic indicators and liver steatosis in Lewis rats. No fibrosis has been observed regardless of diet and 13 cRA treatment.

NAFDL, 13-cRA, fibrosis, HFD

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