To further support the critical role of ER stress in NASH progression and HCC development, knock-outs of another key protein in a gatekeeper, Gp78, an E3 ubiquitin ligase, which degrades unfolded protein in ER, resulted in up-regulation of unfolded protein response (UPR) pathways and SREBP-1 regulating de novo lipogenesis; the model spontaneously developed NASH, and further progressed to HCC in one year [69]. This evidence concerns the gene AMFR and hepatocellular carcinoma.