In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1‐¹³C]Pyruvate and Proton Density Fat Fraction in a Guinea Pig Model of Non‐Alcoholic Fatty Liver Disease Development After Life‐Long Western Diet Consumption

Abstract

Background: Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. Purpose: To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. Study Type: Prospective. Animal Model: Twenty-eight male guinea pigs weaned onto a control diet (N = 14) or WD (N = 14). Field Strength/Sequence: 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. Assessment: Median PDFF was calculated in the liver and hind limbs. [1-13 C]pyruvate dynamic MRS in the liver was quantified by the time-to-peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. Statistical Tests: Unpaired Student's t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. Results: Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. Data Conclusion: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. Level of Evidence: 2 Technical Efficacy Stage: 1

Hyperpolarized carbon 13 MRI in liver diseases: Recent advances and future opportunities

“…34,35 Subsequently, Smith et al quantified the metabolic changes in NAFLD and normal pigs by measuring time to peak (TTP) of HP 13 C pyruvate and its metabolites. 11 They noted the decreased liver lactate TTP in 13 C spectra in NAFLD pigs, indicating an increased rate of lactate production and a disturbance in liver lipid synthesis. Based on these findings, it is anticipated to incorporate HP 13 C MRI in clinical practice to properly understand the underlying mechanisms of NAFLD and eventually guide clinicians to better manage this disease and help its reversal.…”

“…Consecutive studies from Jeong’s group initially explored the time course changes of HP 13 C metabolites in obese and NAFLD rats induced by high‐fat diet (HFD), suggesting the increased levels of alanine and lactate as the useful biomarkers of fatty liver diseases 34,35 . Subsequently, Smith et al quantified the metabolic changes in NAFLD and normal pigs by measuring time to peak (TTP) of HP 13 C pyruvate and its metabolites 11 . They noted the decreased liver lactate TTP in 13 C spectra in NAFLD pigs, indicating an increased rate of lactate production and a disturbance in liver lipid synthesis.…”

“…Pathologically, necrosis is usually the consequence of embolizing feeding hepatic arteries and depriving tumours from nutrients in TAE treatment, which can be easily detected by using another HP 13 C probe, [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate. In general, the conversion rate and concentration of fumarate and its metabolite (i.e., malate) would rapidly change when the tumour cells are in a necrotic condition without intact membrane.…”

“…More recently, new HP 13 C probe, [1,[3][4][5][6][7][8][9][10][11][12][13] C 2 ]ethyl acetoacetate (EAA), has been reported feasible in imaging the metabolism in rats with implanted HCC. 51 It is generally acknowledged that the concentrations and activities of carboxylesterases, an enzyme that turn EAA to acetoacetate (AA), are lower in cancer cells compared to the corresponding normal cells.…”

“…9 By mapping the dynamic conversion between HP 13 C substrates and their metabolic products, for example, [1- 13 C]pyruvate to [1- 13 C]lactate or [1- 13 C]alanine, researchers can obtain additional data beyond routine imaging modalities and form a better understanding of liver pathogenesis. Recent evidence indicates that this technique holds great promise in both diffuse liver diseases [10][11][12] and liver malignancies, [13][14][15] with special focus on detection and diagnosis; assessment of disease progression and prediction of therapeutic responses.…”