Repurposing drugs to target nonalcoholic steatohepatitis

Figure 2 Nonalcoholic fatty liver disease-Kyoto Encyclopedia of Genes and Genomes pathway and mechanisms of disease pathogenesis. Pathway was retrieved from https://http://www.genome.jp/dbget-bin/www_bget?pathway+hsa04932; figure was modified to highlight key molecular processes. This map shows a stage-dependent progression of nonalcoholic fatty liver disease (NAFLD). In the first stage of NAFLD, pathway highlights excess lipid accumulation associated with the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. In addition, two transcription factors, SREBP-1c and PPARα, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. In the second stage, pathway is presented as a consequence of the progression to nonalcoholic steatohepatitis (NASH); the production of reactive oxygen species is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplasmic reticulum (ER) stress, leading to lipid peroxidation. The lipid peroxidation can further cause the production of cytokines [Fas ligand, tumor necrosis factor α (TNF-α), IL-8 and transforming growth factor], promoting cell death, inflammation and fibrosis. The activation of JNK, which is induced by ER stress, TNF-α and FAAs, is also associated with NAFLD progression. Increased JNK promotes cytokine production and initiation of hepatocellular carcinoma. Major organelles involved in the pathogenesis of NASH are also highlighted in the NAFLD-pathway, including mitochondria and mitochondrial dysfunction. In the figure, molecular targets that were further selected to explore protein-chemical interactions are highlighted by red squares. NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; ER: Endoplasmic reticulum; HCC: Hepatocellular carcinoma; NAFL: Nonalcoholic fatty liver; FAAs: Free fatty acids; TNFα: tumor necrosis factor α.