In conclusion, as summarized in Figure 9, our data suggested that liver fat injury induced by HFD caused a significant biliary reaction and SOX9+HNF4α+ biphenotypic HPCs were activated in the fatty liver of mice with enhanced proliferative activity, and Sirt1 plays a vital role in activating HPCs to repair the fatty liver injury and promote liver regeneration through Wnt/β-catenin signal pathway in NAFLD, which might provide a new strategy for fatty liver injury or NAFLD therapy. Here, HNF4A is linked to fatty liver disease.