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Journal of Lipid Research, Vol. 50, 611-622, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

In vivo MRS assessment of altered fatty acyl unsaturation in liver tumor formation of a TGF/c-myc transgenic mouse model^*

J. Griffitts^*,, Y. Tesiram^*, G. E. Reid^,**, D. Saunders^*, R. A. Floyd and R. A. Towner^1,*,

^* Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
Pathology Department, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
Department of Chemistry, Michigan State University, East Lansing, MI 48824
^** Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824
Experimental Therapeutics, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

^* Support for the studies was provided by funding from the Oklahoma Medical Research, the Oklahoma Center for the Advancement of Sciences and Technology (OCAST), grant of fMRI-2, Molecular Image Inc. (Menlo Park, CA), and National Institutes of Health grant RO1CA82506.

Published, JLR Papers in Press, December 8, 2008.

¹ To whom correspondence should be addressed. e-mail: rheal-towner{at}omrf.org

Current detection methods (computed tomography, ultrasound, and MRI) for hepatocarcinogenesis in humans rely on visual confirmation of neoplastic formations. A more effective early detection method is needed. Using in vivo magnetic resonance spectroscopy (MRS), we show that alterations in the integral ratios of the bis-allyl to vinyl hydrogen protons in unsaturated lipid fatty acyl groups correlate with the development of neoplastic formations in vivo in a TGF/c-myc mouse hepatocellular carcinoma (HCC) model. HPLC analysis of the TGF/c-myc mice liver tissue revealed a significant increase in the amount of oleic acid, along with alterations in linoleic and -linolenic acids, as compared with control CD1 mice. Electrospray ionization tandem mass spectrometry analysis indicated a significant increase in the abundance of specific glycerol phosphatidylcholine (GPCho) lipids containing palmitic and oleic acids between control CD1 and TGF/c-myc mice liver tissue extracts. Western blot analysis of the mice liver tissue indicates alterations in the desaturase enzyme stearoyl CoA desaturase (SCD)1, responsible for palmitic and oleic acid formation. Microarray analysis detected alterations in several genes involved with fatty acid metabolism, particularly SCD2, in transgenic mouse liver tissue. In correlation with the HPLC, mass spectrometry, Western blot, and microarray analyses, we are able to confirm the ability of in vivo MRS to detect precancerous lesions in the mouse liver before visual neoplastic formations were detectable by MRI.

Supplementary key words unsaturated fatty acids • tumor lipid metabolism • liver cancer • magnetic resonance spectroscopy • mice

Abbreviations: CSI, chemical shift imaging; DU, degree of unsaturation; FDR, false discovery rate; FADS1, fatty acid desaturase 1; FADS2, fatty acid desaturase 2; GPCho, glycerol phosphatidylcholine; GPE, glycerol phosphatidylethanolamine; HCC, hepatocellular carcinoma; MRS, magnetic resonance spectroscopy; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, precursor ion; ROI, region of interest; SCD, stearoyl CoA desaturase; TE, echo time; TR, relaxation time

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