Pathogenetic pathways in nonalcoholic fatty liver disease: An incomplete jigsaw puzzle

Abstract

Multiple pathways including insulin signaling, JNK1/2 of MAPK signaling, GLP-1R signaling, and NRs affect to maintain the homeostasis of lipid metabolism in normal liver. ERK1/2 and P38 of MAPK signaling pathway antagonistically regulate the auto-phagy of hepatocytes. Functional imbalance of these pathways leads to hepatic stea -tosis by triglyceride increase and autophagy inhibition, together with insulin resistance based on inhibitory phosphorylation of Irs. Liver steatosis provokes lipid peroxidation and ER stress, which result in hepatocyte injury and lobular inflammation. Besides, gut-derived microbial metabolite (eg, LPS) stimulates the TLR-dependent production of proinflammatory cytokines by macrophages. Both hepatic injury and cytokine-induced inflammatory response initiate the occurrence and development of NASH and related fibrosis. On ligand-based TGFBRs activation, HSCs obtain activated phenotype through the TGF-b signaling pathway. But the activation and population of HSCs can be inhibited by NRs and apoptosis, respectively. Abnormalities in these pathways disrupt the balance of ECM production and degradation of the liver, with an outcome of advanced fibrosis and cirrhosis. Despite the present knowledge of path-ogenic pathways, further researches are needed to highlight other ones underlying NAFLD effector cells and related pathological characteristics. Finishing this jigsaw puzzle could make access to the effective prevention and treatment of NAFLD, and keep patients free for NASH and related cirrhosis, and hepatocellular carcinoma.