. Transgenic 6F tomatoes act on the small intestine to prevent systemic infl ammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid. J. Lipid Res. 2013. 54: 3403-3418.
Supplementary key words 6F peptide • apolipoprotein A-I mimetic peptides • atherosclerosis • lysophosphatidic acid • genetically engineered tomato plantsMimetics of apolipoprotein A-I (apoA-I) containing only 18 amino acids showed promise in animal models of disease ( 1, 2 ), and improved HDL function in humans when given orally at high doses despite achieving low plasma peptide levels ( 3 ). However, when high plasma levels were achieved with low doses of peptide given intravenously or by subcutaneous (SQ) injection, no improvement in HDL function was seen ( 4 ). Studies in mice surprisingly suggested that the major site of action for these peptides is in the Abstract We recently reported that levels of unsaturated lysophosphatidic acid (LPA) in the small intestine significantly correlated with the extent of aortic atherosclerosis in LDL receptor-null (LDLR ؊ / ؊ ) mice fed a Western diet (WD). Here we demonstrate that WD increases unsaturated (but not saturated) LPA levels in the small intestine of LDLR ؊ / ؊ mice and causes changes in small intestine gene expression. Confi rmation of microarray analysis by quantitative RT-PCR showed that adding transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F) to WD prevented many WD-mediated small intestine changes in gene expression. If instead of feeding WD, unsaturated LPA was added to chow and fed to the mice: i ) levels of LPA in the small intestine were similar to those induced by feeding WD; ii ) gene expression changes in the small intestine mimicked WD-mediated changes; and iii ) changes in plasma serum amyloid A, total cholesterol, triglycerides, HDLcholesterol levels, and the fast-performance liquid chromatography lipoprotein profi le mimicked WD-mediated changes. Adding Tg6F (but not control tomatoes) to LPA-supplemented chow prevented the LPA-induced changes. We conclude that: i ) WD-mediated systemic infl ammation and dyslipidemia may be in part due to WD-induced increases in small intestine LPA levels; and ii ) Tg6F reduces WD-mediated systemic infl ammation and dyslipidemia by preventing WDinduced increases in LPA levels in the small intestine. -Navab, M., G. Hough, G. M. Buga, F. Su, A. C. Wagner, D. Meriwether, A. Chattopadhyay, F. Gao, V. Grijalva, J. S. Danciger, B. J. Van Lenten, E. Org, A. J. Lusis, C. Pan, G. M. the Laubisch, Castera, and M. K. Grey Abbreviations: CXCL1, chemokine (CXC motif) ligand 1; EV, empty vector tomatoes (transgenic tomatoes constructed with the vector pBI121 containing the GUS gene; 6F,
This work was supported in part bycontaining all L -amino acids; FPLC, fast-performance liquid chromatography; LDLR Ϫ / Ϫ , LDL receptor-null; LPA, lysophosphatidic acid; PA, phosphatidic acid; PPAR, peroxisome proliferatoractivated receptor; RT-qPCR, quantitative RT-PCR ; SAA, serum amyloid A; SQ, subcutaneous; Tg6F, t...