Fig. 2

Molecular mechanisms associated with hepatocyte lipotoxicity and apoptosis. There are 3 major sources of fatty acids in the liver, including dietary intake, self-synthesis from scratch, and catabolism by peripheral adipose tissue. FFA is transported into the hepatocytes to synthesize triglycerides, which leads to hepatic steatosis. Lipotoxicity induces death receptor signaling pathways that recruit caspase 8 to cleave Bid and regulate apoptosis. Excess SFA accumulates in the ER and induces ER stress, which in turn induces the transcription factor CHOP and mediates the onset of JNK. CHOP not only interacts with activated c-jun to upregulate the transcription of the pro-apoptotic BH3 protein, PUMA but also increases the expression of another BH3-only protein, Bim, which synergistically activates the pro-apoptotic protein, Bax. Bim and PUMA synergistically activate the pro-apoptotic protein Bax, which causes mitochondrial dysfunction and induces apoptosis through the release of cyt C and the activation of caspases proteases. Mitochondrial dysfunction, on the other hand, also leads to the overproduction of reactive ROS, which causes oxidative stress and further induces cell death. FFA, free fatty acid; SFA, saturated fatty acid; ER, endoplasmic reticulum; oxygen species