Figure 2.

The contribution of mutant PNPLA3 to the risk of NASH and fibrosis. PNPLA3 mutation results in increased oxidative stress and fatty acid oxidation which subsequently leads to accumulation of highly toxic lipid metabolites (e.g. diacylglycerol, ceramides, sphingomyelin, sphingosine). These lipotoxic metabolites trigger immune activation and inflammation via key signaling pathways mediated by p-JNK and p-STAT3, and ultimately activation of several fibrogenic pathways such as those for TGF-β1, α-SMA, Col1 and 3. Col1, collagen I; Col3, collagen III; FA, fatty acid; DAG, diacylglycerol; GSH, GSSG, glutathione-disulfide; glutathione; JNK, c-Jun activated kinase; KDSR, 3-ketodihydrosphingosine reductase; SMA, α-smooth muscle actin; STAT3, signal transducer and activator of transcription, TGF-β, transforming growth factor β.