Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars.

OBJECTIVE: Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS: We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS: Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS: Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.

Frontal Cortex Myo-Inositol Is Associated with Sleep and Depression in Adolescents: A Proton Magnetic Resonance Spectroscopy Study.

AIM: This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the neurochemistry of the frontal cortex in adolescents with symptoms of sleep and depression. METHODS: Nineteen non-medicated adolescent boys (mean age 16.0 years; 9 clinical cases with depression/sleep symptoms and 10 healthy controls) underwent 1H MRS at 3 T. MR spectra were acquired from the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex, and frontal white matter. Concentrations of N-acetyl aspartate, total creatine, choline-containing compounds, total glutamine plus glutamate, and myo-inositol (mI) were compared in the 2 subgroups, and correlated with sleep and clinical measures in the total sample. Sleep was assessed with self-report questionnaires and ambulatory polysomnography recordings. RESULTS: Concentrations of mI were lower in both frontal cortical regions among the depressed adolescents than in controls. No statistically significant differences in other metabolite concentrations were observed between the subgroups. Frontal cortex mI concentrations correlated negatively with depression severity, subjective daytime sleepiness, insomnia symptoms, and the level of anxiety, and correlated positively with total sleep time and overall psychosocial functioning. The correlations between mI in the ACC and total sleep time as well as daytime sleepiness remained statistically significant when depression severity was controlled in the analyses. CONCLUSION: Lower frontal cortex mI may indicate a disturbed second messenger system. Frontal cortical mI may thus be linked to the pathophysiology of depression and concomitant sleep symptoms among maturing adolescents. Short sleep and daytime sleepiness may be associated with frontal cortex mI independently from depression.

Metabolic profile of liver damage in non-cirrhotic virus C and autoimmune hepatitis: A proton decoupled 31P-MRS study.

PURPOSE: To study liver 31P MRS, histology, transient elastography, and liver function tests in patients with virus C hepatitis (HCV) or autoimmune hepatitis (AIH) to test the hypothesis that 31P MR metabolic profile of these diseases differ. MATERIALS AND METHODS: 25 patients with HCV (n=12) or AIH (n=13) underwent proton decoupled 31P MRS spectroscopy performed on a 3.0T MR imager. Intensities of phosphomonoesters (PME) of phosphoethanolamine (PE) and phosphocholine (PC), phosphodiesters (PDE) of glycerophosphoethanolamine (GPE) and glycerophosphocholine (GPC), and γ, α and ß resonances of adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide phosphate (NADPH) were determined. Liver stiffness was measured by transient elastography. Inflammation and fibrosis were staged according to METAVIR from biopsy samples. Activities of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALT) and thromboplastin time (TT) were determined from serum samples. RESULTS: PME had a stronger correlation with AST (z=1.73, p=0.04) and ALT (z=1.77, p=0.04) in HCV than in AIH patients. PME, PME/PDE, PE/GPE correlated positively and PDE negatively with inflammatory activity. PE, PC and PME correlated positively with liver function tests. CONCLUSION: 31P-MRS suggests a more serious liver damage in HCV than in AIH with similar histopathological findings. 31P-MRS is more sensitive in detecting inflammation than fibrosis in the liver.

31Phosphorus magnetic resonance spectroscopy of the liver for evaluating inflammation and fibrosis in autoimmune hepatitis.

BACKGROUND: Liver biopsy is the gold standard in evaluating inflammation and fibrosis in autoimmune hepatitis. AIMS: In search of non-invasive follow-up tools in autoimmune hepatitis, we evaluated 31phosphorus magnetic resonance spectroscopy (31P MRS). METHODS: Twelve consecutive AIH patients (mean age 42.8 years, 10 women) underwent liver biopsy, routine laboratory liver function tests, which were compared to findings in 31P MRS and transient elastography (TE). RESULTS: Phosphoenolpuryvate (PEP) correlated with the grade of inflammation (r = 0.746, p = .005) and thromboplastin time (r = 0.592, p = .043). It also differentiated patients with active inflammation from patients without (t = 3.781, p = .009). There was no correlation between PEP and aminotransferase or immunoglobulin G levels. The phosphoethanolamine (PE)/phosphocholine (PC) ratio, PE/glyserophosphoethanolamine (GPE) ratio and PC/[total phosphomonoester (PME) + phosphodiester (PDE)] ratios correlated with immunoglobulin G (r = 0.764, p = .006; r = 0.618, p = .043; and r= -0.636, p = .035, respectively). PME/PDE and PE/GPE correlated with fibrosis (r = 0.668, p = .018 and r = 0.604, p = .037). PE/GPE also differentiated F3 from F0-2 patients (t = 3.810, p = .003). Phosphorus metabolites did not correlate with TE results and TE did not correlate with liver histology or laboratory parameters. CONCLUSIONS: 31P MRS seems to detect active inflammation and advanced fibrosis in AIH patients. TE was ineffective in fibrosis quantification.

Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD.

To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

Evidence for abnormal glucose uptake or metabolism in thalamus during acute hyperglycaemia in type 1 diabetes--a 1H MRS study.

Acute hyperglycaemia impairs cognitive function. It is however not known, whether different brain regions are equally exposed to glucose during acute hyperglycemia or whether the brain is able to adjust its glucose uptake or metabolism in response to blood glucose fluctuation. We studied the effect of acute hyperglycaemia on the brain glucose concentration in seven men with type 1 diabetes with daily glucose fluctuations of 11 +/- 3 mmol/l, and in eleven age-matched non-diabetic men. Glucose was quantified with proton magnetic resonance spectroscopy in three different brain regions at baseline (fasting glycaemia) and twice during a 2 h hyperglycaemic clamp with plasma glucose increase of 12 mmol/l. The increase in brain glucose during acute hyperglycaemia in the non-diabetic group was: cortex (2.7 +/- 0.9 mmol/l) > thalamus (2.3 +/- 0.7 mmol/l) > white matter (1.7 +/- 0.7 mmol/l, P = 0.021 vs. cortex) and in the diabetic group: cortex (2.0 +/- 0.7 mmol/l) > white matter (1.3 +/- 0.7 mmol/l) > thalamus (1.1 +/- 0.4 mmol/l, P = 0.010 vs. cortex). In the diabetic group, the glucose increase in the thalamus was attenuated compared to the non-diabetic participants (P = 0.011). In conclusion, the increase of glucose during acute hyperglycaemia seems to be dependent on the brain tissue type. The high exposure of cortex to excess glucose and the altered glucose uptake or metabolism in the thalamus may thus contribute to hyperglycaemia related cognitive dysfunction.

PRESS echo time behavior of triglyceride resonances at 1.5T: detecting omega-3 fatty acids in adipose tissue in vivo.

AIM: This study investigated the impact of fatty acid (FA) composition on the echo time behavior of triglyceride resonances in a clinical setting. The feasibility of (1)H NMR spectroscopy to detect these resonances was also evaluated in human adipose tissue in vivo. METHOD: Ten edible oils chosen to cover a wide spectrum of FA compositions were used as phantom material. The detailed FA composition and intrinsic proton spectra of the oils were characterized by gas chromatography and high-resolution (1)H NMR spectroscopy (11.7T), respectively. The detailed echo time behavior of the oils were subsequently measured by (1)H NMR spectroscopy in a clinical scanner (1.5T) using PRESS. The effect of temperature was investigated in five oils. RESULTS: The olefinic (5.3 ppm) and diallylic (2.8 ppm) resonances exhibited distinct J-modulation patterns independent of oil FA composition. The methylene resonance (1.3 ppm) displayed an exponential decay, with the apparent T(2) showing a weak positive correlation with oil unsaturation (R=0.628, P=0.052), probably a result of changes in viscosity. For the methyl resonance (0.9 ppm), oils high in omega-3 FA displayed a markedly different J-modulation pattern compared to non-omega-3 oils. The characteristic J-modulation of the omega-3 methyl group could be attributed to the phase behavior of the omega-3 methyl triplet signal (all triplet lines in-phase at TE of 135 ms), a result of the omega-3 methyl end forming a first order spin system. The omega-3 methyl outer triplet line at 1.08ppm of the TE=140 ms spectrum was found to be useful for determining the omega-3 content of the oils (R=0.999, standard error of estimate (SE) 0.80). The olefinic and diallylic proton resonance (measured at TE=50 ms) areas correlated with the olefinic (R=0.993, SE 0.33) and diallylic (R=0.997, SE 0.19) proton contents calculated from the GC data. Information derived from long echo time spectra (TE=200) demonstrated good correlations to GC data and showed no change with increasing temperature (and T(2)). In (1)H NMR spectra (1.5T) of adipose tissue in five healthy subjects, the analytically important olefinic and diallylic resonances were clearly resolved with a coefficient of variation of 1.6% and 8.4%, respectively, for repeated measurements. The characteristic phase behavior of the omega-3 methyl outer triplet line at 1.08 ppm could also be detected at very long echo times (470 and 540 ms). CONCLUSION: Fatty acid composition has an impact on the echo time behavior of triglyceride resonances. Long TE spectra can resolve omega-3 FA in adipose tissue in vivo. These findings will benefit long TE studies of tissue lipids.

Risk for metabolic syndrome predisposes to alterations in the thalamic metabolism.

Risk factors for the metabolic syndrome (MetS) affect brain function and associate with asymptomatic brain infarctions in healthy individuals. We studied whether MetS risk factors alter cerebral metabolism. Eighteen non-smoking men (36 +/- 6years) were stratified into two groups according to their risk of developing the MetS. Individuals in the Risk group had a family history of type 2 diabetes, were pre-obese, had mild hypertension and higher fasting plasma glucose and serum insulin compared to the Control group with no risk factors. N-acetyl aspartate, choline, total creatine (tCr), myo-inositol, and glucose were studied in the thalamus, frontal cortex, and frontal white matter with proton magnetic resonance spectroscopy. The plasma glucose was 13% higher (p < 0.01) in the Risk group, but the brain glucose levels were comparable between the groups. In the Control group, the thalamic tCr correlated with the thalamic glucose level (r = 0.81, p = 0.015). In the Risk group, the tCr was 17% higher (p = 0.006) and correlated with the fasting plasma glucose concentration (r = 0.78, p = 0.013), but not with the thalamic glucose level. In conclusion, the increased tCr level in the Risk group suggests that a family history of type 2 diabetes together with MetS risk factors alters thalamic energy metabolism.