Hepatocyte-targeted siTAZ therapy lowers liver fibrosis in NASH diet-fed chimeric mice with hepatocyte-humanized livers

Nonalcoholic steatohepatitis (NASH) is emerging as the most common cause of liver disease. Although many studies in mouse NASH models have suggested therapies, translation to humans is poor, with no approved drugs for NASH. One expla-nation may lie in differences between mouse and human hepa-tocytes. We used NASH diet-fed chimeric mice reconstituted with human hepatocytes (hu-liver mice) to test a mechanism -based hepatocyte-targeted small interfering RNA (siRNA), GalNAc-siTaz, shown previously to block the progression to fibrotic NASH in mice. Following ablation of endogenous he-patocytes, male mice were reconstituted with human hepato-cytes from a single donor with the rs738409-C/G PNPLA3 risk variant, resulting in X95% human hepatocyte reconstitu-tion. The mice were then fed a high-fat choline-deficient L-amino acid-defined diet for 6 weeks to induce NASH, fol-lowed by six weekly injections of GalNAc-siTAZ to silence he-patocyte-TAZ or control GalNAc-siRNA (GalNAc-control) while still on the NASH diet. GalNAc-siTAZ lowered human hepatic TAZ and IHH, a TAZ target that promotes NASH fibrosis. Most important, GalNAc-siTAZ decreased liver inflammation, hepatocellular injury, hepatic fibrosis, and pro-fibrogenic mediator expression versus GalNAc-control, indi-cating that GalNAc-siTAZ decreased the progression of NASH in mice reconstituted with human hepatocytes. In conclusion, silencing TAZ in human hepatocytes suppresses liver fibrosis in a hu-liver model of NASH.