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Mitochondrial function and immunometabolism in Down Syndromeĭown's syndrome (DS) is the most common autosomal trisomy among live births. Moreover, we are studying gene expression changes in hepatocellular carcinoma (HCC) and compounds selectively cytotoxic to liver tumor cells. Our goal is to evaluate the biological effect of new PPARa ligands in order to identify effective and safe lipid-lowering agents for hypercholesterolemia and dyslipidemia.
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We are investigating molecular mechanisms underlying gene expression of mitochondrial proteins in different conditions. Mitochondrial functions - such as lipid metabolism and TCA cycle - are essential for hepatic metabolic activities and detoxification. Dysregulation of nutrient metabolism is a key step during the progression of chronic liver disease inducing an inflammatory status, cell damage, and impaired hepatic insulin signaling, which leads to insulin resistance. The liver is the metabolic center of the mammalian body by regulating complex biochemical functions such as nutrient homeostasis (proteins, carbohydrates and lipids) and xenobiotic detoxification. Liver cell biology in physiological and pathological processes Our goal is to deepen understanding of the citrate pathway role in chronic inflammatory diseases and in the wider context of immunometabolism. This function of the citrate pathway in pro-inflammatory signaling provides new insights on the relationship between energy metabolism and inflammation. Moreover, CIC and ACLY activities are required for inflammatory response in macrophages. Recently, we have found that lipopolysaccharides as well as TNFα and INFγ cytokines activate both SLC25A1 and ACLY genes in immune cells.
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We refer to CIC plus ACLY as “citrate pathway”. A second metabolic product generated from the cleavage of citrate is oxaloacetate (OAA), which is reduced to malate by cytosolic malate dehydrogenase and converted to pyruvate via malic enzyme in a reaction that generates cytosolic NADPH plus H +. In the cytosol, citrate is cleaved by ATP-citrate lyase (ACLY) to acetyl-CoA, which is the precursor for fatty acid and sterol biosynthesis and the universal donor for acetylation reactions. After its synthesis in mitochondria, citrate can be transported into the cytosol by the citrate carrier (CIC), a member of the mitochondrial carrier family encoded by the SLC25A1 gene. Citrate is a key intermediate metabolite.