Figure 2.

The indirect pathways regulating hepatic stellate cell (HSC) activation in steatohepatitis. Metabolic insults such as hyperinsulinemia/hyperglycemia lead to the activation of transcriptional coactivator with PDZ-binding motif (TAZ) in hepatocytes. Increased hepatocyte expression of TAZ in nonalcoholic steatohepatitis (NASH) but not simple steatosis directly leads to HSC activation through the release of Indian hedgehog (Ihh) and promotes hepatocyte injury and inflammation that may indirectly promote HSC activation. Notch activation by cell-surface ligands on a neighboring cell leads to a Sox9-dependent increase in osteopontin (OPN) secretion to activate HSCs. HSC activation occurs through direct interactions between stressed or dead hepatocytes (i.e., apoptosis, necrosis, or necroptosis) and HSCs. This may be through the release of profibrogenic damage-associated molecular patterns. High mobility group box 1 (HMGB1) is released by injured hepatocytes to mediate the recruitment of neutrophils. Monocyte infiltration into the liver is primarily controlled by C–C chemokine receptors (CCR2) and its ligand CCL2, which may serve as therapeutic targets in NASH. Adiponectin modulates Kupffer cell function via reduction of Toll-like receptor 4 (TLR4) signaling, and directly stimulates M1→M2 polarization.