Role of amino acid metabolism and autophagy in chemical-induced abnormal lipid metabolism and fatty liver

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Metabolic disorders are frequently caused by nutritional, behavioral and metabolic factors as well as by diverse chemical exposure. Together with inflammation and endothelial dysfunction, fatty liver is one of the related disorders in metabolic syndrome. Chemicals induce fatty liver by disturbing normal lipid metabolism including enhanced lipogenesis and free fatty acid uptake as well as decreased fatty acid oxidation and VLDL secretion. As a novel mechanism of ethanol- and diet-induced fatty liver, we report that downregulation of 3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme involved in the serine synthesis, and low hepatic serine level contribute to the development of fatty liver disease through suppressing SIRT1. Autophagy is one of the essential catabolic pathways activated in response to nutrient deprivation. Recently, lipid droplets have been identified as a substrate for autophagy. Some NSAIDs induces hepatic lipid accumulation and fatty liver by disturbing lysosomal degradation of PLIN2, a substrate for chaperone-mediated autophagy. Identification of novel mediators of fatty liver will contribute to the development of strategies for the treatment and prevention of the disease.