[en] Background: Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute pancreatitis. The present study was undertaken to investigate the impact of hypertriglyceridemia on the mitochondrial, sub-mitochondrial and cellular proteomes in the hepatocytes of a hypertriglyceridemic transgenic mouse model overexpressing the human apolipoproteinC-III.
Methods: Quantitative comparative proteomics (2D-DIGE) was carried out in both “low-expressor” (LE) and “high-expressor” (HE) mice, respectively exhibiting moderate and severe HTG, to characterize the effect of the TG plasma level on the proteomic response.
Results: The mitoproteome analysis revealed the occurrence of a large-scale adaptation in transgenic mice consisting of a general down-regulation of matricial proteins and up-regulation of inner membrane proteins. Remarkably, the magnitude of these proteomic changes appears to strongly depend on the TG plasma level. Altogether, our different analyses indicate that, in HE mice, the capacity of several metabolic pathways is altered to promote the availability of acetyl-CoA, glycerol-3-phosphate, ATP and NADPH for de novo TG biosynthesis. The up-regulation of several cytosolic ROS detoxifying enzymes also tend to confirm that the cytoplasm of HTG mice is subjected to oxidative stress as previously stated. The up-regulation of cytosolic ferritin indicates that iron over-accumulation could take place in the cytosol of HE mice hepatocytes and contribute to (i) enhance oxidative stress and (ii) promote cellular proliferation.
Conclusions: The present analyses demonstrate that important TG dose-responsive metabolic adaptations are set up in human apolipoproteinC-III-overexpressing mice. Our results indicate that these adaptations could support the higher TG production rates which have been previously reported in this HTG model, and also suggest that cytosolic oxidative stress may result from FFA over-accumulation, iron overload and enhanced activity of some ROS-producing catabolic enzymes.
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