Non-mammalian fat-1 gene prevents neoplasia when introduced to a mouse hepatocarcinogenesis model

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.

Experimental Evidence ofω-3 Polyunsaturated Fatty Acid Modulation of Inflammatory Cytokines and Bioactive Lipid Mediators: Their Potential Role in Inflammatory, Neurodegenerative, and Neoplastic Diseases

“…Subsequently, several other studies demonstrated decreased liver tumorigenesis in fat-1 mice. In a transgenic hepatoma model containing double mutations in c-myc and TGF- α a constitutive increase in ω -3 PUFA tissue content led to protection from liver tumor development that was associated with a decrease in NF- κ B levels [123]. In the diethylnitrosamine (DEN) model of chemically induced liver carcinogenesis a tumor suppression effect of increased ω -3 PUFA tissue status was demonstrated in the fat-1 mice as well, with lowered plasma TNF- α levels and decreased liver COX-2 expression [31].…”

Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease

“…This resulted in a murine model exhibiting increased levels of n -3 PUFAs with diminished n -6 PUFA concentrations within different organs, including the brain ( 15 ). The Fat-1 mouse was investigated in various disease settings and benefi cial effects of the transgene were reported on liver neoplasia ( 17 ) and atherosclerotic lesions ( 18 ) as well as in the prevention of cerebral seizures induced by pentylenetetrazol ( 19 ). In addition, increased spatial learning performances, enhanced dendritic spine density, and neurogenesis were observed in this model ( 20 ).…”

Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice

“…The severe imbalance between n−6 and n−3 fatty acids (n−6/n−3>10) in the modern Western diet and human body tissue has been thought to contribute to today’s increased risk of diseases, including cancer [14], [18]. Evidence from recent studies using the transgenic fat-1 mouse model, which can endogenously convert n−6 to n−3 fatty acids and has a balanced n−6/n−3 ratio in its body tissues [40], strongly supports this notion [41]–[48]. These studies have demonstrated that decreasing the tissue ratio of n−6/n−3 can significantly reduce the formation and growth of various cancers, which is associated with reduced levels of cancer-related eicosanoids and genes [41]–[48], suggesting that the tumor - promoting effect of increased D6D activity can be diminished by decreasing tissue n−6/n−3 fatty acid ratio.…”