ContextSaturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms.ObjectiveTo investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans.DesignDouble-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction.SettingGeneral community.ParticipantsMen and women who are overweight or have obesity (n = 61).InterventionMuffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet.Main Outcome MeasuresLean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots.ResultsBy design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat, or total body fat compared with PUFA. SFA consistently increased, whereas PUFA reduced circulating ceramides, changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction.ConclusionsSFA markedly induces liver fat and serum ceramides, whereas dietary PUFA prevents liver fat accumulation and reduces ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.

The effect of a variety of cytokines on lipid metabolism in 3T3 Li mouse fibroblasts and adipocytes was studied. Uptake of [3H]acetate by adipocytes and heparinreleasable lipoprotein lipase activity was inhibited after treatments of the cells with picomolar concentrations of recombinant human tumor necrosis factor a (rHuTNF-a), human tumor necrosis factor 13 (rHuTNF-f, also called lymphotoxin), murine interferon-y (rMuIFN-y), and a human hybrid interferon-a [rHuIFN-a2/aj (Bgl I)]. Recombinant human interferon-y (rHuIFN-y), natural human colony-stimulating factor (HuCSF), and human interleukin 2 (HuIL-2) had no effect. Similar though less-marked suppression of [3H~acetate uptake by cytokines was seen in 3T3 Li fibroblasts. Cytokines inhibited the incorporation of [3H]acetate into both membrane and storage lipids in the adipocytes. In addition to blocking lipid uptake and synthesis, rHuTNF-a and -(3, and rMuIFN-y stimulated the release of free fatty acid into the medium from adipocytes. Binding studies suggest that rHuTNF-a and rHuTNF-P compete for the same cell-surface receptor on 3T3 Li adipocytes, while rMuIFN-y binds to a separate receptor.The binding of rTNF-a to both adipocytes and fibroblasts can be significantly enhanced by preexposure of the cells to rMuIFN-y. There appear to be both high-and low-affinity receptors for rHuTNF-a on adipocytes, whereas fibroblasts exhibit a single class of high-affinity receptors. These results suggest that a variety of structurally distinct cytokines possess lipid mobilization activity, which may be of critical importance to the host in defense against infection or malignancy.The invasion of the body by viruses, bacteria, or parasites usually elicits an integrated host response that kills and removes the infectious agents and provides immunity against future challenges. Much of the host response is modulated by a class of inducible proteins called cytokines (1-3). It is now clear that there are many distinct host cytokines that can be produced by a wide variety of cell types, including epithelial cells, fibroblasts, tumor cells, and particularly lymphocytes (lymphokines) and macrophages (monokines) (4-6). Tumor necrosis factors (TNFs), interleukins (ILs), and a-, ,B, and -interferons (IFN-a, -(3, and -y) are representative and well-characterized cytokines. Although there is considerable structural and functional heterogeneity among these families of cytokines, they all appear to have roles in the regulation of host immunity and inflammation (7-12). When administered parenterally at high doses they can be toxic, and many of the symptoms associated with the common cold and influenza such as fever, nausea, and muscle aches can be induced by the administration of pure cytokines (13,14). Unraveling the sequence of cytokine actions that occur during the host response to infection is very complex because (i) cytokines regulate the production of one another (15-17), (ii) an individual cell may produce many different cytokines (18, 19), and (iii) different cytokines may hav...

Because a correlation between tau pathology and the clinical symptoms of Alzheimer disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-18 F-THK5117. Methods: Nine subjects (5 with AD, 4 with mild cognitive impairment) received a 90-min dynamic (S)-18 F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. Volume-ofinterest (VOI)-based analysis was performed using plasma-input models; single-tissue and 2-tissue (2TCM) compartment models and plasma-input Logan and reference tissue models; and simplified reference tissue model (SRTM), reference Logan, and SUV ratio (SUVr). Cerebellum gray matter was used as the reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan, and SUVr. Regionally averaged voxel values were compared with VOI-based values from the optimal reference tissue model, and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40-and 60-min data were analyzed. Results: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R 2 5 0.99, slope 5 0.96). SRTM binding potential (BP ND ) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R 2 5 1.00, slope ≈ 1.00) whereas SUVr 70-90 -1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R 2 5 0.99, slope 5 1.03). SUVr 70-90 -1 values were almost 3 times higher than BP ND values in white matter and 1.5 times higher in gray matter. Simulations showed poorer accuracy and precision for SUVr 70-90 -1 values than for the other reference methods. SRTM BP ND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min. Conclusion: SRTM BP ND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-18 F-THK5117 DVR-1 parametric images with the greatest accuracy and precision and with a much lower white-matter signal than seen with SUVr 70-90 -1 images.

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