Abstract 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 explanation may lie in inherent differences between mouse and human hepatocytes. We used NASH diet-fed chimeric mice reconstituted with human hepatocytes (hu-liver mice) to test a mechanism-based hepatocyte-targeted siRNA, GalNAc-siTaz, shown previously to block the progression to fibrotic NASH in mice. Mice were reconstituted with human hepatocytes following ablation of endogenous hepatocytes, resulting in ~95% human hepatocyte reconstitution. The mice were then fed a high-fat choline-deficient Lamino acid-defined diet for 6 weeks to induce NASH, followed by six weekly injections of GalNAc-siTAZ to silence hepatocyte-TAZ or control GalNAc-siRNA (GalNAc-control) while still on the NASH diet. The results revealed that GalNAc-siTAZ lowered human hepatic TAZ and IHH, the major TAZ target that promotes liver fibrosis in NASH. Most importantly, GalNAc-siTAZ decreased liver inflammation, hepatocellular injury, hepatic fibrosis, and profibrogenic mediator expression, and profibrotic NOTCH vs. GalNAc-control, indicating 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. Impact and Implications No drugs have yet been approved for NASH, which is a leading cause of liver disease worldwide. The findings here provide support for this therapeutic strategy of using hepatocyte-targeted siTAZ to decrease NASH progression. More generally, the study illustrates how hu-liver NASH mice can be used to evaluate therapeutic hepatocyte-targeted siRNAs to help prioritize future testing in human NASH.

Hepatocyte-Targeted siTAZ Therapy Lowers Liver Fibrosis in NASH Diet-Fed Chimeric Mice with Hepatocyte-Humanized Livers