FIG. 9.

Schematic showing the pivotal role of p62/SQSTM1 in injury of the steatotic liver. Steatosis-associated reduction of p62/SQSTM1 induces FasL/Fas in the steatotic liver. Along with exogenous FasL, this directly causes post-PH necrotic and apoptotic acute liver injury in, respectively, a redox-dependent and redox-independent manner. Reduction of p62/SQSTM1 reduces Keap-1/Nrf-2 binding, which suppresses the expression of antioxidant molecules (catalase, MnSOD, Ref-1, HO-1, TRX, and GPx) and, therefore, makes the liver susceptible to OS. Furthermore, the hypo-responsiveness of Akt enhances necrotic and apoptotic injury, along with the reduced expression of antioxidant molecules and anti-apoptotic molecules (Bcl-2, Bcl-xL, and FLIP), respectively. These mechanisms may collectively underlie steatosis-associated liver injury in the mouse. GPx, glutathione peroxidase; HO-1, heme oxygenase 1; Keap-1, Kelch-like ECH-associated protein 1; TRX, thioredoxin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars