Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges [RNA-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 transcriptome sequencing on liver tissues of fed and fasted Ripk1fl/fl and Ripk1Δhep mice, respectively. A total of 10 samples were collected in 4 groups, including 2 replicates per group of fed mice and 3 replicates per group of fasting mice.