Figure 3.

Dysregulated lipid metabolism plays a role in the development of NASH. Altered lipophagy, lipolysis and de novo lipogenesis in the liver contribute to NASH development through fat accumulation, and subsequent inflammation and fibrosis. A “first hit” of increased FFAs leads to accumulation of LDs in hepatocytes, a condition known as NAFLD. Additional “hits”, including inflammation and insulin resistance contribute to steatohepatitis (NASH), characterized by hepatocyte ballooning, lobular inflammation and fibrosis. Liver-resident macrophages (KCs) may acquire a pro-inflammatory phenotype due to the excess hepatic fat burden and mediate the inflammatory response through the recruitment of immune cells from the periphery. In response to hepatic injury, normally quiescent HSCs become activated by various signals. Enhanced lipophagy of vitamin A-storing LDs provides energy for HSCs activation, leading to hepatic fibrosis through HSCs-mediated collagen deposition.