ANTI-STEATOTIC EFFECTS OF DOCOSAEXAENOIC ACID AND HYDROXYTYROSOL IN THE LIVER OF MICE FED A HIGH-FAT DIET: PPAR-A AND NRF2 UP-REGULATION, AND OF SRBP-1C AND NF-KB DOWN-REGULATION
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Date
2017
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Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal accumulation of lipids, being insulin resistance, oxidative stress, inflammation and a drastic depletion of n-3 LCPUFA the main expressions of the disease. Docosahexaenoic acid (DHA, 22:6, n-3) controls liver lipid metabolism by stimulation of lipolysis and inhibition of lipogenesis and Hydroxytyrosol (HT) exhibits strong tissue cytoprotective effects. Objetive: To evaluate the molecular mechanisms involved in the protective effects of a mixture of DHA and HT (DHA /HT), to prevent the development of NAFLD induced by high-fat diet (HFD) in mice. Methods: Male C57BL/6J mice received control diet (CD) (10% fat) or high fat diet (HFD - 60% fat), non-supplemented/ supplemented of DHA (50 mg per kg per day)/ HT (5 mg per kg per day) for 12 weeks. Parameters studied included liver histology (optical microscopy), activity of hepatic antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase (by spectrophotometry), oxidative stress indicators (glutathione, thiobarbituric acid reactants, and the antioxidant capacity of plasma), gene expression assays for PPAR-α, Nrf2, SREBP-1c and NF-κB (qPCR and ELISA), and LCPUFA profiles in liver (gas-liquid chromatography). Results: Results: HFD induced (i) liver steatosis (increasing total fat, triacylglycerols and free fatty acid content), (ii) higher fasting serum glucose, insulin levels and HOMA index, total cholesterol, triacylglycerols, TNF-α and IL-6, (iii) liver and plasma oxidative stress enhancement, (iv) depletion of n-3 LCPUFA content of liver phospholipids, increasing lipogenic and reducing lipolytic enzyme activities (v) down-regulation of PPAR-α and Nrf2, and (vi) up-regulation of SREBP-1c and NF-kB (gene expression and DNA binding activity). These changes were either reduced (p < 0.05) or normalized (compared to CD) in animals feed HFD supplemented with DHA/HT. Conclusions: DHA/HT intervention exerts anti-steatotic effects underling antioxidants and anti-inflammatory responses by improving insulin sensitivity and recovering the lipolytic/lipogenic status of the liver altered by HFD, being PPAR-α and Nrf2 up-regulation, together with SREBP-1c and NF-κB down-regulation important molecular mechanisms involved in the protective action of DHA/HT. These effects may support the potential therapeutic use of DHA/HT supplementation in the treatment of liver steatosis induced by nutritional factors and/or other etiologies. Keywords: Anti-steatotic effects; docosahexaenoic acid; hydroxytyrosol; antioxidant effects ; antiinflammatory effects