Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges [scRNA-seq]

In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1Δhep) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1Δhep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1Δhep mice during fasting, highlighting the increased recruitment of macrophages to the liver. We performed single-cell RNA sequencing of liver non-parenchymal cells isolated from Ripk1Δhep or Ripk1fl/fl mice upon fasting. A total of 22274 single-cell transcriptomes (10374 Ripk1fl/fl; 11900 Ripk1Δhep) were obtained.