REGULATION OF INTESTINAL GENES BY AN ORAL PEPTIDE REDUCES SYSTEMIC INFLAMMATION AND ATHEROGENESIS
Mohamad Navab, Ph.D., David Geffen School of Medicine, University of California, Los Angeles, CA, USA
A high fat, high cholesterol diet (Western diet, WD) increases the levels of the potent growth promoter unsaturated lysophosphatidic acid (LPA) in small intestine and plasma of LDLR-/- mice. Supplementing mouse chow with unsaturated LPA produced dyslipidemia and inflammation. WD increased the expression of the genes Acadl, Acot1 and Angptl4 while reducing that of Reg3g. The transgenic plant reversed the changes in gene expression. We now report that supplementing chow with unsaturated LPA resulted in aortic atherosclerosis, which was ameliorated by adding a transgenic 6F plant powder. Supplementing chow with lysophosphatidylcholine (LysoPC) 18:1 resulted in dyslipidemia similar to that seen on adding LPA 18:1 to chow. A specific inhibitor of autotaxin (PF8380) significantly ameliorated the dyslipidemia induced by LysoPC 18:1. Supplementing chow with LysoPC 18:1 markedly increased the levels of unsaturated LPA in small intestine, plasma and liver. This increase was ameliorated by PF8380 indicating an autotaxin-dependent conversion of LysoPC 18:1 to LPA 18:1. Adding LysoPC 18:0 to chow increased levels of LPA 18:0 in small intestine, plasma and liver. This was not altered by PF8380 indicating that conversion of LysoPC 18:0 to LPA 18:0 was not autotaxin-dependent. We therefore conclude that a) autotaxin mediates the conversion of unsaturated LysoPC to LPA, and b) intestinally-derived unsaturated LPA can cause atherosclerosis in LDLR-/- mice.