Non-mammalian fat-1 gene prevents neoplasia when introduced to a mouse hepatocarcinogenesis model: Omega-3 fatty acids prevent liver neoplasia |
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Authors: | J Griffitts D Saunders YA Tesiram GE Reid A Salih S Liu TA Lydic JV Busik JX Kang RA Towner |
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Institution: | 1. Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA;2. Pathology Department, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;3. Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA;4. Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, USA;5. Department of Physiology, Michigan State University, East Lansing, MI 48824, USA;6. Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129-2000, USA |
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Abstract: | We investigated the effect of a non-mammalian omega-3 desaturase in a mouse hepatocarcinogenesis model. Mice containing double mutations (DM) in c-myc and TGF-α (transforming growth factor-α), leading to liver neoplasia, were crossed with mice containing omega-3 desaturase. MRI analysis of triple mutant (TM) mice showed the absence of neoplasia at all time points for 92% of mice in the study. Pathological changes of TM (TGFα/c-myc/fat-1) mouse liver tissue was similar to control mouse liver tissue. Magnetic resonance spectroscopy (MRS) measurements of unsaturated fatty acids found a significant difference (p < 0.005) between DM and TM transgenic (Tg) mice at 34 and 40 weeks of age. HPLC analysis of mouse liver tissue revealed markedly decreased levels of omega-6 fatty acids in TM mice when compared to DM (TGFα/c-myc) and control (CD1) mice. Mass spectrometry (MS) analysis indicated significantly decreased 16:0/20:4 and 18:1/20:4 and elevated 16:0/22:6 fatty acyl groups in both GPCho and GPEtn, and elevated 16:0/20:5, 18:0/18:2, 18:0/18:1 and 18:0/22:6 in GPCho, within TM mice compared to DM mice. Total fatty acid analysis indicated a significant decrease in 18:1n9 in TM mice compared to DM mice. Western blot analysis of liver tissue showed a significant (p < 0.05) decrease in NF-κB (nuclear factor-κB) levels at 40 weeks of age in TM mice compared to DM mice. Microarray analysis of TM versus DM mice livers at 40 weeks revealed alterations in genes involved in cell cycle regulation, cell-to-cell signaling, p53 signaling, and arachidonic acid (20:4) metabolism. Endogenous omega-3 fatty acids were found to prevent HCC development in mice. |
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Keywords: | HCC Hepatocellular carcinoma GPCho glycerophosphatidylcholine GPEtn glycerophosphatidylethanolamine IACUC Institutional Animal Care and Use Committee FLASH fast low angle shot TE echo time TR relaxation time DM double mutant TM triple mutant Tg transgenic |
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