ABSTRACT
Squalene is the main unsaponifiable component of virgin olive oil, the main source of dietary fat in Mediterranean diet, traditionally associated with a less frequency of cardiovascular diseases. In this study, two experimental approaches were used. In the first, New Zealand rabbits fed for 4 weeks with a chow diet enriched in 1% sunflower oil for the control group, and in 1% of sunflower oil and 0.5% squalene for the squalene group. In the second, APOE KO mice received either Western diet or Western diet enriched in 0.5% squalene for 11 weeks. In both studies, liver samples were obtained and analyzed for their squalene content by gas chromatography-mass spectrometry. Hepatic distribution of squalene was also characterized in isolated subcellular organelles. Our results show that dietary squalene accumulates in the liver and a differential distribution according to studied model. In this regard, rabbits accumulated in cytoplasm within small size vesicles, whose size was not big enough to be considered lipid droplets, rough endoplasmic reticulum, and nuclear and plasma membranes. On the contrary, mice accumulated in large lipid droplets, and smooth reticulum fractions in addition to nuclear and plasma membranes. These results show that the squalene cellular localization may change according to experimental setting and be a starting point to characterize the mechanisms involved in the protective action of dietary squalene in several pathologies.
Subject(s)
Cell Membrane/metabolism , Diet, Mediterranean , Disease Models, Animal , Liver/metabolism , Non-alcoholic Fatty Liver Disease/prevention & control , Nuclear Envelope/metabolism , Squalene/therapeutic use , Animals , Biological Transport , Cell Membrane/pathology , Cytoplasmic Vesicles/metabolism , Cytoplasmic Vesicles/pathology , Cytosol/metabolism , Cytosol/pathology , Diet, High-Fat/adverse effects , Diet, Western/adverse effects , Endoplasmic Reticulum, Rough/metabolism , Endoplasmic Reticulum, Rough/pathology , Endoplasmic Reticulum, Smooth/metabolism , Endoplasmic Reticulum, Smooth/pathology , Lipid Droplets/metabolism , Lipid Droplets/pathology , Lipid Metabolism , Liver/pathology , Male , Mice, Knockout, ApoE , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Nuclear Envelope/pathology , Rabbits , Species Specificity , Squalene/metabolismABSTRACT
The alkynyl gold(I) derivative [Au(C≡CPh)(PTA)] (PTA=1,3,5-triaza-7-phosphaadamantane) induces apoptosis in colorectal carcinoma tumour cells (Caco-2) without affecting to normal enterocytes. [Au(C≡CPh)(PTA)] is a slight lipophilic drug, stable in PBS (Phosphate Buffered Saline) and able to bind BSA (Bovin Serum Albumin) by hydrophobic interactions. Once inside the cell, [Au(C≡CPh)(PTA)] targets seleno proteins such as Thioredoxin Reductase 1, increasing ROS (Reactive Oxygen Species) levels, reducing cell viability and proliferation and inducing mitochondrial apoptotic pathway, pro-apoptotic and anti-apoptotic protein imbalance, loss of mitochondrial membrane potential, cytochrome c release and activation of caspases 9 and 3. Moreover, unlike other metal-based drugs such as cisplatin, [Au(C≡CPh)(PTA)] does not target nucleic acid, reducing the risk of side mutation in the DNA. In consequence, our results predict a promising future for [Au(C≡CPh)(PTA)] as a chemotherapeutic agent for colorectal carcinoma.