Figure 7. A schematic diagram of “two hit” hypothesis associated with TLR7, autophagy, IGF-1 and lipid peroxidation.

The “two hit” hypothesis explains gradually progression of NAFLD. Lipid accumulation, indicate as “first hit” produces lipid peroxidation products such as MDA, and 4-HNE indicate as “second hit” gradually. The “second hit” reduced TLR7 and autophagy serially. This reduction of autophagy inhibits IGF-1 release from liver to blood and accumulates massive IGF-1 in liver. Massive presence of IGF-1 in liver induced massive MDA, and 4-HNE for progression of NAFLD. TLR7-Autophagy signaling usually protects against “first hit” and “second hit” via regulation of IGF-1 contents in the liver. TLR7 agonist, imiquimod and autophagy activator, rapamycin reversed previous phenomenon. In conclusion, TLR7 prevents progression of NAFLD, and serves a pivotal role in both the first and the second hits that lead to NAFLD.