The Impact of Lipid Accumulation on Mitochondrial Metabolism in the Liver

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High rates of new lipid synthesis (de novo lipogenesis) and dysfunctional mitochondrial metabolism are central features of non-alcoholic fatty liver disease (NAFLD). However, it is not clear whether sustained induction of de novo lipogenesis will alter the activity of mitochondrial oxidative networks during progressive severity of NAFLD. We tested the alterations in mitochondrial metabolism in livers with high rates of de novo lipogenesis. Male mice (C57BL/6J) were reared on normal chow with either regular drinking water (NW) or 30% fructose in drinking water (FW) to induce lipogenesis, for 2-wks. Liver mitochondria were isolated from fed and overnight fasted (~16-hrs) mice. Mitochondria were allowed to respire at 37C for either zero or 10-min. Changes in mitochondrial metabolites were determined via gas chromatography-mass spectrometry (GC-MS). Plasma samples were used for GC-MS based targeted metabolomics. Liver tissue was utilized to profile lipogenic gene expression. After 2-wks of treatments, lipogenic gene expression in the liver (Acc, Fasn, Elovl6) was significantly higher in the FW group (p≤0.05). While plasma β-hydroxybutyrate levels were induced by overnight fasting in both the groups, the fed-to-fasted fold change was significantly higher in the FW group compared to the NW group (p=0.001). Furthermore, levels of mitochondrial TCA cycle intermediates (pyruvate, citrate, fumarate) were induced with fasting in FW compared to NW (p≤0.07) after 10-mins of mitochondrial respiration. Taken together, these results suggest that the mitochondrial oxidative function is higher in livers sustaining higher rates of de novo lipogenesis.



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