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

J Griffitts,Y Tesiram,G.E Reid,D Saunders,R.A Floyd,R.A Towner

doi:10.1194/jlr.m800265-jlr200

Abstract

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 TGFalpha/c-myc mouse hepatocellular carcinoma (HCC) model. HPLC analysis of the TGFalpha/c-myc mice liver tissue revealed a significant increase in the amount of oleic acid, along with alterations in linoleic and gamma-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 TGFalpha/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.

Highlights

Current detection methods for hepatocarcinogenesis in humans rely on visual confirmation of neoplastic formations
The findings of this study have shown that magnetic resonance spectroscopy (MRS) is able to detect in vivo alterations in phospholipid unsaturated fatty acyl hydrogens in a transgenic mouse model of hepatocellular carcinoma (HCC) that correlates with neoplastic lesion formation
Significant alterations in the levels of unsaturated of fatty acyl lipids were noted as early as 26 weeks of age in the transgenic mice, a time point where MRI, the standard diagnostic imaging technique, was only able to detect neoplasms in a few cases

Summary

Introduction

Current detection methods (computed tomography, ultrasound, and MRI) for hepatocarcinogenesis in humans rely on visual confirmation of neoplastic formations. 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 TGFa/c-myc mouse hepatocellular carcinoma (HCC) model. 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.—Griffitts, J., Y. The techniques currently used for diagnosis of liver cancer rely on imaging modalities (MRI, computed tomography, and ultrasound) that, at the highest sensitivity, are able to detect evidence of neoplasia when there is a formation of at least 1 mm. We have utilized MRI in this study for visual confirmation of neoplastic tissue formations in the TGFa/c-myc mouse liver tumor model.

Methods

Results

Conclusion