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• W2171750689 abstract "The assessment of liver lipid content and composition is needed in preclinical research to investigate steatosis and steatosis-related disorders. The purpose of this study was to quantify in vivo hepatic fatty acid content and composition using a method based on short echo time proton magnetic resonance spectroscopy (MRS) at 7 Tesla. A mouse model of glycogen storage disease type 1a with inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc−/−) mice and control mice were fed a standard diet or a high-fat/high-sucrose (HF/HS) diet for 9 months. In control mice, hepatic lipid content was found significantly higher with the HF/HS diet than with the standard diet. As expected, hepatic lipid content was already elevated in L-G6pc−/− mice fed a standard diet compared with control mice. L-G6pc−/− mice rapidly developed steatosis which was not modified by the HF/HS diet. On the standard diet, estimated amplitudes from olefinic protons were found significantly higher in L-G6pc−/− mice compared with that in control mice. L-G6pc−/− mice showed no noticeable polyunsaturation from diallylic protons. Total unsaturated fatty acid indexes measured by gas chromatography were in agreement with MRS measurements. These results showed the great potential of high magnetic field MRS to follow the diet impact and lipid alterations in mouse liver. The assessment of liver lipid content and composition is needed in preclinical research to investigate steatosis and steatosis-related disorders. The purpose of this study was to quantify in vivo hepatic fatty acid content and composition using a method based on short echo time proton magnetic resonance spectroscopy (MRS) at 7 Tesla. A mouse model of glycogen storage disease type 1a with inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc−/−) mice and control mice were fed a standard diet or a high-fat/high-sucrose (HF/HS) diet for 9 months. In control mice, hepatic lipid content was found significantly higher with the HF/HS diet than with the standard diet. As expected, hepatic lipid content was already elevated in L-G6pc−/− mice fed a standard diet compared with control mice. L-G6pc−/− mice rapidly developed steatosis which was not modified by the HF/HS diet. On the standard diet, estimated amplitudes from olefinic protons were found significantly higher in L-G6pc−/− mice compared with that in control mice. L-G6pc−/− mice showed no noticeable polyunsaturation from diallylic protons. Total unsaturated fatty acid indexes measured by gas chromatography were in agreement with MRS measurements. These results showed the great potential of high magnetic field MRS to follow the diet impact and lipid alterations in mouse liver. Glycogen storage disease type 1 (GSD 1) is an autosomal recessive metabolic disorder resulting in severe impairment of glucose production and large accumulation of lipids within hepatocytes (steatosis) (1Chou J.Y. Jun H.S. Mansfield B.C. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy.Nat. Rev. Endocrinol. 2010; 6: 676-688Crossref PubMed Scopus (152) Google Scholar, 2Froissart R. Piraud M. Boudjemline A.M. Vianey-Saban C. Petit F. Hubert-Buron A. Eberschweiler P.T. Gajdos V. Labrune P. Glucose-6-phosphatase deficiency.Orphanet J. Rare Dis. 2011; 6: 27Crossref PubMed Scopus (133) Google Scholar). The phenotype of GSD 1 results from a defect in the glucose-6 phosphatase (G6Pase) complex, leading to severe hypoglycemia due to the loss of endogenous glucose production. Despite a strict diet, patients with GSD 1 develop hepatomegaly and steatosis and may develop, with age, hepatocellular adenoma that can ultimately evolve into hepatocellular carcinoma (3Rake J.P. Visser G. Labrune P. Leonard J.V. Ullrich K. Smit G.P. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I).Eur. J. Pediatr. 2002; 161: S20-S34Crossref PubMed Google Scholar, 4Heller S. Worona L. Consuelo A. Nutritional therapy for glycogen storage diseases.J. Pediatr. Gastroenterol. Nutr. 2008; 47: S15-S21Crossref PubMed Google Scholar). Recently, a viable mouse model of GSD 1a with a liver-specific deletion of G6Pase catalytic subunit (L-G6pc−/−) has been generated and validated (5Mutel E. Abdul-Wahed A. Ramamonjisoa N. Stefanutti A. Houberdon I. Cavassila S. Pilleul F. Beuf O. Gautier-Stein A. Penhoat A. et al.Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas.J. Hepatol. 2011; 54: 529-537Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). GSD 1a mice exhibit hepatic pathological features very similar to those observed in GSD 1a patients. The accumulation of lipids in the liver relates to the buildup of neutral lipids, such as triglycerides (TGs) and cholesterol esters, stored as lipid droplets in hepatocytes and leading to hepatic steatosis. This fat accumulation may originate from a) peripheral fat stored in adipose tissue that flows to the liver as plasma nonesterified fatty acids, b) fatty acids newly made within the liver through de novo lipogenesis, and c) dietary fatty acids (6Donnelly K.L. Smith C.I. Schwarzenberg S.J. Jessurun J. Boldt M.D. Parks E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.J. Clin. Invest. 2005; 115: 1343-1351Crossref PubMed Scopus (2395) Google Scholar, 7Postic C. Girard J. The role of the lipogenic pathway in the development of hepatic steatosis.Diabetes Metab. 2008; 34: 643-648Crossref PubMed Scopus (220) Google Scholar). Steatosis is highly linked to the development of metabolic diseases such as obesity or type 2 diabetes, but it can also result from genetic disorders impacting lipid and glucose metabolism such as in GSD 1a, α1-antitrypsin deficiency, or tyrosinemia type 1. Recent studies suggest a crucial importance of hepatic fatty acid composition in the metabolic consequences of steatosis. Indeed, the harmful effects of several fatty acids, and particularly, of palmitate on insulin signaling are well documented (8Matsuzaka T. Atsumi A. Matsumori R. Nie T. Shinozaki H. Suzuki-Kemuriyama N. Kuba M. Nakagawa Y. Ishii K. Shimada M. et al.Elovl6 promotes nonalcoholic steatohepatitis.Hepatology. 2012; 56: 2199-2208Crossref PubMed Scopus (126) Google Scholar, 9Ricchi M. Odoardi M.R. Carulli L. Anzivino C. Ballestri S. Pinetti A. Fantoni L.I. Marra F. Bertolotti M. Banni S. et al.Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes.J. Gastroenterol. Hepatol. 2009; 24: 830-840Crossref PubMed Scopus (416) Google Scholar). In rats, the enrichment of oleate in the diet is associated with improved insulin sensitivity (10Tardif N. Salles J. Landrier J.F. Mothe-Satney I. Guillet C. Boue-Vaysse C. Combaret L. Giraudet C. Patrac V. Bertrand-Michel J. et al.Oleate-enriched diet improves insulin sensitivity and restores muscle protein synthesis in old rats.Clin. Nutr. 2011; 30: 799-806Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Interestingly, the overexpression of a constitutively active form of the lipogenic factor, carbohydrate response element binding protein (ChREBP), improves glycemic control and restores hepatic insulin sensitivity in obese and diabetic mice despite an exacerbation of hepatic lipid accumulation. These improvements are associated with an increased oleate/palmitate ratio in the livers of mice overexpressing ChREBP (11Benhamed F. Denechaud P.D. Lemoine M. Robichon C. Moldes M. Bertrand-Michel J. Ratziu V. Serfaty L. Housset C. Capeau J. et al.The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans.J. Clin. Invest. 2012; 122: 2176-2194Crossref PubMed Scopus (279) Google Scholar). These studies illustrate that it is important to detect lipids accumulating in steatosis but also to profile fatty acids in order to predict damages to the organ. To date, a liver biopsy is necessary to analyze the fatty acid composition, commonly performed by gas chromatography (GC), a technique requiring the extraction and preparation of tissue samples (12Kotronen A. Seppänen-Laakso T. Westerbacka J. Kiviluoto T. Arola J. Ruskeepää A.L. Yki-Järvinen H. Oresic M. Comparison of lipid and fatty acid composition of the liver, subcutaneous and intra-abdominal adipose tissue, and serum.Obesity (Silver Spring). 2010; 18: 937-944Crossref PubMed Scopus (130) Google Scholar). However, a liver biopsy is an invasive and painful technique that can lead to false negative results (13Ratziu V. Charlotte F. Heurtier A. Gombert S. Giral P. Bruckert E. Grimaldi A. Capron F. Poynard T. Sampling variability of liver biopsy in nonalcoholic fatty liver disease.Gastroenterology. 2005; 128: 1898-1906Abstract Full Text Full Text PDF PubMed Scopus (1510) Google Scholar), and is not suitable for longitudinal studies. While 1H-magnetic resonance spectroscopy (MRS) has extensively been used as a noninvasive reference method to assess total fat content, recent studies have demonstrated its ability to assess in vivo TG composition (14Corbin I.R. Furth E.E. Pickup S. Siegelman E.S. Delikatny E.J. In vivo assessment of hepatic triglycerides in murine non-alcoholic fatty liver disease using magnetic resonance spectroscopy.Biochim. Biophys. Acta. 2009; 1791: 757-763Crossref PubMed Scopus (38) Google Scholar). In animal studies, MRS has been used to assess diet impact on lipid composition in the liver (15Garbow J.R. Lin X. Sakata N. Chen Z. Koh D. Schonfeld G. In vivo MRS measurement of liver lipid levels in mice.J. Lipid Res. 2004; 45: 1364-1371Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar) and adipose tissue (16Mosconi E. Fontanella M. Sima D.M. Van Huffel S. Fiorini S. Sbarbati A. Marzola P. Investigation of adipose tissues in Zucker rats using in vivo and ex vivo magnetic resonance spectroscopy.J. Lipid Res. 2011; 52: 330-336Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 17Branca R.T. Warren W.S. In vivo NMR detection of diet-induced changes in adipose tissue composition.J. Lipid Res. 2011; 52: 833-839Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar) as well as in the muscle of a diabetic mouse model (18Ye Q. Danzer C.F. Fuchs A. Krek W. Mueggler T. Baltes C. Rudin M. Longitudinal evaluation of intramyocellular lipids (IMCLs) in tibialis anterior muscle of ob/ob and ob/+ control mice using a cryogenic surface coil at 9.4 T.NMR Biomed. 2011; 24: 1295-1301Crossref PubMed Scopus (9) Google Scholar). Many other animal models are available to investigate steatosis, such as the genetic model ob/ob mouse. The ob/ob mouse model develops steatosis spontaneously and has been well studied by 1H-MRS (19Calderan L. Marzola P. Nicolato E. Fabene P.F. Milanese C. Bernardi P. Giordano A. Cinti S. Sbarbati A. In vivo phenotyping of the ob/ob mouse by magnetic resonance imaging and 1H-magnetic resonance spectroscopy.Obesity (Silver Spring). 2006; 14: 405-414Crossref PubMed Scopus (39) Google Scholar, 20Lee, H. S., Cai, Q. Y., Min, K. N., Park, J. K., Kwak, T. H., Jeong, K. H., Hong, K. S., . 2010. In vivo monitoring of treatment effect of cryptotanshinone for non-alcoholic fatty liver disease in mice (Abstract in ISMRM-ESMRMB Joint Annual Meeting. Stockholm, Sweden, May 1–7, 2010).Google Scholar, 21Peng X.G. Ju S. Qin Y. Fang F. Cui X. Liu G. Ni Y. Teng G.J. Quantification of liver fat in mice: comparing dual-echo Dixon imaging, chemical shift imaging, and 1H-MR spectroscopy.J. Lipid Res. 2011; 52: 1847-1855Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 22Ye Q. Danzer C.F. Fuchs A. Wolfrum C. Rudin M. Hepatic lipid composition differs between ob/ob and ob/+ control mice as determined by using in vivo localized proton magnetic resonance spectroscopy.MAGMA. 2012; 25: 381-389Crossref PubMed Scopus (21) Google Scholar). Mice fed a high-fat or a high-fructose diet were also reported with steatosis (23Ackerman Z. Oron-Herman M. Grozovski M. Rosenthal T. Pappo O. Link G. Sela B.A. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction.Hypertension. 2005; 45: 1012-1018Crossref PubMed Scopus (185) Google Scholar, 24Gauthier M.S. Favier R. Lavoie J.M. Time course of the development of non-alcoholic hepatic steatosis in response to high-fat diet-induced obesity in rats.Br. J. Nutr. 2006; 95: 273-281Crossref PubMed Scopus (89) Google Scholar). At high magnetic fields [≥3 Tesla (T)], which allows a better spectral dispersion, 1H-MRS has also been used to characterize lipid accumulation and lipid composition in a rat model of liver fibrosis (25Cheung J.S. Fan S.J. Gao D.S. Chow A.M. Yang J. Man K. Wu E.X. In vivo lipid profiling using proton magnetic resonance spectroscopy in an experimental liver fibrosis model.Acad. Radiol. 2011; 18: 377-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar), or to evaluate fat content in diabetic obese rats (26Kuhlmann J. Neumann-Haefelin C. Belz U. Kalisch J. Juretschke H.P. Stein M. Kleinschmidt E. Kramer W. Herling A.W. Intramyocellular lipid and insulin resistance: a longitudinal in vivo 1H-spectroscopic study in Zucker diabetic fatty rats.Diabetes. 2003; 52: 138-144Crossref PubMed Scopus (108) Google Scholar) and mice (22Ye Q. Danzer C.F. Fuchs A. Wolfrum C. Rudin M. Hepatic lipid composition differs between ob/ob and ob/+ control mice as determined by using in vivo localized proton magnetic resonance spectroscopy.MAGMA. 2012; 25: 381-389Crossref PubMed Scopus (21) Google Scholar). Recently, this technique was correlated with histology and TG level (21Peng X.G. Ju S. Qin Y. Fang F. Cui X. Liu G. Ni Y. Teng G.J. Quantification of liver fat in mice: comparing dual-echo Dixon imaging, chemical shift imaging, and 1H-MR spectroscopy.J. Lipid Res. 2011; 52: 1847-1855Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar) in order to compare these techniques for fat quantification in mice. At clinical fields (≤3 T), the TG composition of subcutaneous human adipose tissue has been estimated and validated with GC (27Lundbom J. Hakkarainen A. Fielding B. Soderlund S. Westerbacka J. Taskinen M.R. Lundbom N. Characterizing human adipose tissue lipids by long echo time (1)H-MRS in vivo at 1.5 Tesla: validation by gas chromatography.NMR Biomed. 2010; 23: 466-472Crossref PubMed Scopus (48) Google Scholar). In this paper, localized short echo time (TE) in vivo MRS and GC analysis was used to evaluate the content and composition of fatty liver in L-G6pc−/− mice as well as in control C57BL/6J mice. L-G6pc−/− and control mice were fed either a standard diet or a high-fat/high-sucrose (HF/HS) diet to compare genetically induced steatosis and diet-induced steatosis. In vitro validation of the proposed method was first conducted before its application. The method was based on respiratory-gated localized short TE and an automated time-domain quantification method employing a nonlinear least-squares algorithm that fits the time-domain signal to a Voigt model function and uses multiple random starting values and bounds. In this study, a whole MRS-based procedure was described and validated to quantify noninvasively the hepatic fat content and composition, and determine the possible impact of the diet on the hepatic lipid composition in L-G6pc−/− and control mice. The induction of the G6pc exon 3 was performed at adult age (7–8 weeks of age) by treating female B6.SACreERT2.G6pclox/lox mice with tamoxifen (5Mutel E. Abdul-Wahed A. Ramamonjisoa N. Stefanutti A. Houberdon I. Cavassila S. Pilleul F. Beuf O. Gautier-Stein A. Penhoat A. et al.Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas.J. Hepatol. 2011; 54: 529-537Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). After G6pc deletion, mice were fed either a standard diet (3.1% lipids, 60% carbohydrates, 16.1% proteins) (n = 15) or a HF/HS diet (36.1% lipids, 35% carbohydrates, 19.8% proteins) (n = 12) during 9 months. The detailed composition of the diet was previously described by Moraes et al. (28Moraes R.C. Blondet A. Birkenkamp-Demtroeder K. Tirard J. Orntoft T.F. Gertler A. Durand P. Naville D. Begeot M. Study of the alteration of gene expression in adipose tissue of diet-induced obese mice by microarray and reverse transcription-polymerase chain reaction analyses.Endocrinology. 2003; 144: 4773-4782Crossref PubMed Scopus (123) Google Scholar). Two groups of control mice (C57Bl6/J; Charles Rivers Laboratories, France) fed a standard (n = 5) or a HF/HS (n = 12) diet were also analyzed. All animals were housed in the animal facility of Université Lyon 1 (Animaleries Lyon Est Conventionnelle et SPF), under controlled temperature (22°C), with a 12 h light-12 h dark cycle. Mice had free access to food and water. The experiments were conducted according to the procedures approved by the Institutional Animal Care and Ethical Committee of Lyon 1 University. Following MR examinations, a subset of mice was killed by dislocation of the cervical vertebrae and liver tissue samples were rapidly removed and frozen using tongs previously chilled in liquid N2 to analyze lipids by GC and to quantify TG levels using a Biomérieux colorimetric kit. Magnetic resonance imaging and magnetic resonance spectroscopic data were collected on a 7 Tesla Biospec 70/20 system (Bruker, Ettlingen, Germany) equipped with a shielded gradient set (400 mT·m−1 maximum gradient amplitude and 120 mm inner diameter) and a 1H transmit-receive quadrature coil (Rapid Biomedical, Würzburg, Germany) with 32 mm inner diameter. Animals were anesthetized by inhalation of 2% isoflurane. The body temperature was maintained inside the magnet at 37°C by warm water circulation. A pressure sensor was used to monitor the respiratory cycle. A point-resolved spectroscopy (PRESS) sequence was used for localized 1H-MRS with a short TE (16 ms). The effective repetition time (TR), which had to be a multiple of the respiratory period of the mouse, was set to be greater than 3 s to minimize T1 relaxation effects. The prescription of the voxel (3 × 3 × 3 mm3) localization within the right lobe of the liver in an area free of large hepatic vessels and surrounding fat, was done on the T2-weighted RARE (Rapid Acquisition with Relaxation Enhancement) images that were previously acquired with the following parameters: TE, 40.4 ms; field of view, 30 × 30 mm2; matrix, 256 × 192; 36 or 48 slices; slice thickness, 0.5 mm; RARE factor, 8. The sequence was synchronized with respiration using balanced acquisitions over several respiratory periods with an effective TR of about 6 s (29Baboi L. Pilleul F. Milot L. Lartizien C. Poncet G. Roche C. Scoazec J.Y. Beuf O. Magnetic resonance imaging follow-up of liver growth of neuroendocrine tumors in an experimental mouse model.Magn. Reson. Imaging. 2010; 28: 264-272Crossref PubMed Scopus (6) Google Scholar). Localized first- and second-order shim terms were adjusted manually to reach a line width for the water resonance inferior to 60 Hz. For each mouse, the MRS signals were acquired without water suppression (8 accumulations, 1 min scan time) and with VAPOR (Variable Pulse Power and Optimized Relaxation delays) water suppression (128 accumulations, 7 min scan time). Spectra without water suppression were also collected over a range of TEs from 21 to 100 ms (TE: 21/26/31/36/100 ms) in order to calculate the different spin-spin relaxation times (T2) of the resonances of both in vitro and in vivo spectra. For validation purposes, in vitro MRS measurements were also collected from one sample filled with sunflower oil, with known composition (6% methyl palmitate, 3% methyl stearate, 35% methyl oleate, 50% methyl linoleate, 3% methyl linolenate, and 3% methyl arachidate) using a unique TE PRESS sequence (TE/TR: 16/5,000 ms). The MRS signals were processed in the time domain after being corrected for zero- and first-order phase. The quantification procedure, called the Multiple Starting Value method, implemented in Matlab R2011b, is based on a nonlinear least-squares algorithm that fits the time-domain signal to a combination of Voigt model functions (30Ratiney, H., Bucur, A., Sdika, M., Beuf, O., Pilleul, F., Cavassila, S., . 2008. Effective Voigt model estimation using multiple random starting values and parameter bounds settings for in vivo hepatic 1H magnetic resonance spectroscopic data (Abstract in 2008 IEEE International Symposium on Biomedical Imaging: From Nano to Macro. Paris, France, May 14–17, 2008).Google Scholar). Each Voigt function is characterized by the combination of Lorentzian and Gaussian functions. The model function used in the fitting procedure is a weighted sum of damped sinusoids which are Voigt lines after Fourier transform. The weighting factors involved in the linear combination of the different damped sinusoids are called the amplitude parameters in the time domain which is, in the frequency domain, the usual peak area. Thus, the free model parameters are the amplitudes, Lorentzian and Gaussian damping factors, and frequencies of each Voigt lineshape and the zero-order phase. The algorithm uses multiple random starting values and bounds for the frequency and damping factor parameters. The frequency parameters were constrained within an interval of ±10 Hz around their starting values. The Lorentzian and Gaussian damping factors were constrained to be lower than 200 Hz in vitro and 350 Hz in vivo, the zero-order phase was constrained within an interval of ±3° around 0°. In this manuscript, the estimated amplitude parameter of the Voigt lineshape resonating at the frequency f is written “f” and refers also, in the interests of simplifying notation, to intensity of the resonance arising at the frequency f. For the in vitro measurements, 10 resonances were identified and quantified: methyl group (0.9 ppm), methylene group (1.3 ppm), β-methylene to carboxylic group (1.6 ppm), allylic group (2 ppm), α-methylene to carboxylic group (2.25 ppm), diallylic group (2.8 ppm), glycerol backbone (4.07 ppm, 4.23 ppm, 5.2 ppm), and olefinic group (5.3 ppm). For in vivo measurements, no contribution to the resonances other than lipid was assumed, since lipid resonances are predominant in MR liver spectra. Nine resonances were then identified, 5.3 ppm and 5.2 ppm being considered as a single broad resonance (Table 1). Each resonance was modeled with one component in the model-function except for 1.3 ppm, which was fitted with one or two components in vivo and in vitro and for the water at 4.7 ppm which was fitted with one or two components in vivo. Water amplitude was used as internal reference. Reliability of the parameter estimates was assessed using Cramér Rao theory. Amplitude estimates with Cramér Rao lower bounds above 20% were discarded from the subsequent analysis.TABLE 1Assignment of the nine chemical groups and their corresponding chemical shift from in vivo 1H-MRS spectraChemical GroupChemical Shift (ppm)DescriptionCH30.9Methyl(CH2)n1.3MethyleneCH2CH2CO1.6β-Methylene to carboxyl groupCH2CH=CHCH2CH22.00AllylicCH2CH2CO2.25α-Methylene to carboxyl groupCH=CHCH2CH=CH2.8Diallylic (polyunsaturated)CH2-COO4.07Glycerol backboneCH2-COO4.23Glycerol backboneCH=CH5.3OlefinicAcquired in a mouse liver at 7 T (Fig. 3) with a short-TE PRESS sequence (TE/TR: 16/3,000 ms). Open table in a new tab Acquired in a mouse liver at 7 T (Fig. 3) with a short-TE PRESS sequence (TE/TR: 16/3,000 ms). Spectra were quantified with the same algorithm as described previously. Then, T2 decay of each resonance according to the TE was modeled with a mono-exponential decay and T2 correction was performed as described by (15Garbow J.R. Lin X. Sakata N. Chen Z. Koh D. Schonfeld G. In vivo MRS measurement of liver lipid levels in mice.J. Lipid Res. 2004; 45: 1364-1371Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Each resonance was corrected in intensity with the corresponding estimated T2 relaxation time. No T1 relaxation times were estimated for additional correction because for TR > 3,000 ms (in vivo) and TR = 5,000 ms (in vitro), all resonances were considered fully relaxed. The total lipid (TL) index reflects the hepatic fat content and was calculated as the relative ratio of resonance intensities from methylene and methyl chemical groups to water. Indexes of saturation and unsaturation were evaluated according to (14Corbin I.R. Furth E.E. Pickup S. Siegelman E.S. Delikatny E.J. In vivo assessment of hepatic triglycerides in murine non-alcoholic fatty liver disease using magnetic resonance spectroscopy.Biochim. Biophys. Acta. 2009; 1791: 757-763Crossref PubMed Scopus (38) Google Scholar, 31van Werven J.R. Marsman H.A. Nederveen A.J. Ten Kate F.J. van Gulik T.M. Stoker J. Hepatic lipid composition analysis using 3.0-T MR spectroscopy in a steatotic rat model.Magn. Reson. Imaging. 2012; 30: 112-121Crossref PubMed Scopus (22) Google Scholar, 32Cobbold J.F. Patel J.H. Goldin R.D. North B.V. Crossey M.M. Fitzpatrick J. Wylezinska M. Thomas H.C. Cox I.J. Taylor-Robinson S.D. Hepatic lipid profiling in chronic hepatitis C: an in vitro and in vivo proton magnetic resonance spectroscopy study.J. Hepatol. 2010; 52: 16-24Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) as described in Table 2. The ratio of methylene resonance intensity to methyl resonance intensity described the saturated component (SC) of hepatic fatty acids. The fraction of unsaturation (FU) is expressed with the ratio of allylic to α-methylene to carboxylic group resonance intensities.TABLE 2Indexes of fatty acid composition evaluated from analysis of proton MRS spectra.Index of Fatty AcidFatty Acid ComponentTL(“1.3”+“0.9”)/(“1.3”+“0.9”+“4.7”)SC(3/2) × (“1.3”/“0.9”)FU(1/2) × (“2”/“2.25”)TUFA“5.3”/(“1.3”+“4.7”)TUFI(3/4) × (“2”/“0.9”)TUBI(3/2) × (“5.3”/“0.9”)The estimated amplitude of the time-domain function resonating at the frequency f is written “f”. Open table in a new tab The estimated amplitude of the time-domain function resonating at the frequency f is written “f”. The amount of total unsaturation was estimated using two indexes: the total unsaturated fatty acids (TUFAs) and the total unsaturated fatty acid index (TUFI). On the one hand, TUFA was calculated as the ratio of olefinic (methine) resonance contribution to water and methylene resonance contributions. This index reflects the amount of total (poly and mono) unsaturated fatty acids relative to the water content and TL. A subsidiary index is the relative TUFA (rTUFA) which gives the TUFA relative to the amount of total fatty acids. On the other hand, TUFI was defined as the ratio of allylic to methylene resonance intensities. While TUFA is directly proportional to the number of double bonds found in the lipids presents in the volume of interest, TUFI will be directly proportional to the number of unsaturated chains, whether they are mono or poly unsaturated fatty acid chains. The ratio of olefinic resonance intensity to methyl resonance intensity is called the total unsaturated bond index (TUBI) and approximates the average number of double bonds for the unsaturated fatty acids. Fatty acid assay was performed as described in (33Zadravec D. Brolinson A. Fisher R.M. Carneheim C. Csikasz R.I. Bertrand-Michel J. Boren J. Guillou H. Rudling M. Jacobsson A. Ablation of the very-long-chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity.FASEB J. 2010; 24: 4366-4377Crossref PubMed Scopus (71) Google Scholar). Following homogenization of liver samples in methanol/5 mM EGTA (2:1, v/v), lipids corresponding to an equivalent of 1 mg of liver were extracted in the presence of glyceryl triheptadecanoate (0.5 g) as an internal standard. The lipid extract was transmethylated with 1 ml of boron trifluoride in methanol (1:20, v/v) for 150 min at 100°C, evaporated to dryness, and the fatty acid methyl esters (FAMEs) were extracted with hexane/water (3:1). The organic phase was evaporated to dryness and dissolved in 50 μl ethyl acetate. One microliter of FAME was analyzed by gas-liquid chromatography on a 5890 Hewlett-Packard system using a Famewax fused-silica capillary column (30 m, 0.32 mm internal diameter, 0.25 mm film thickness; Restek, Belfast, UK). Oven temperature was programmed from 110 to 220°C at a rate of 2°C/min, and the carrier gas was hydrogen (0.5 bar). The injector and the detector were at 225 and 245°C, respectively. Identification of the FAMEs was based upon retention times obtained for methyl ester standards. In order to obtain comparable results between the GC and MRS methodologies, the proportions of the chemically equivalent groups of protons were calculated from the GC fatty acid data according to (27Lundbom J. Hakkarainen A. Fielding B. Soderlund S. Westerbacka J. Taskinen M.R. Lundbom N. Characterizing human adipose tissue lipids by long echo time (1)H-MRS in vivo at 1.5 Tesla: validation by gas chromatography.NMR Biomed. 2010; 23: 466-472Crossref PubMed Scopus (48) Google Scholar), with normalization with each mass of each fatty acid respectively, and then fatty acid indexes were derived. Wilcoxon rank tests were performed to determine the statistical difference between the groups and P = 0.05 was considered to be significant. Correlation between MRS and GC estimated parameters were evaluated with Pearson coefficient correlation. Tukey box plots (34Tukey J.W. Exploratory Data Analysis. Addison-Wesley, Reading, MA1977Google Scholar) were chosen for plotting data. On each b" @default.
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• W2171750689 date "2013-07-01" @default.
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• W2171750689 title "In vivo hepatic lipid quantification using MRS at 7 Tesla in a mouse model of glycogen storage disease type 1a" @default.
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