GSE115766
Rapid recapitulation of non-alcoholic steatohepatitis upon loss of HCF-1 function in mouse hepatocytes [RNA-seq]
Background and Aims: Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X linked gene Hcfc1, is an epigenetic co-regulator important for mouse development and cell proliferation, including during liver regeneration. Here, we examine the role of HCF-1 in adult tissue physiology using, as model, the resting mouse liver. Methods: We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1hepKO), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1 hepKO/Y males by four days. In heterozygous Hcfc1hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. Results: The livers with Hcfc1hepKO/Y hepatocytes displayed a 21–24-day terminal non-alcoholic fatty liver (NAFL) followed by non-alcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1 alpha protein levels, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1hepKO/Y liver pathology. Interestingly, although HCF-1 binds to over 5000 transcriptional start sites in the resting liver, expression of only a minor subset of the associated genes was affected by HCF-1 loss. Conclusion: HCF-1 is essential for proper liver physiology likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice represent models for the study of NASH and NAFLD resolution. Overall design: Mouse liver samples from male WT, male KO, and female heterorygotes were collected from day zero to day 14 after Tamoxifen injection. Replicates were generated for all male samples from day zero to day nine, and for male KO at day 14 as well. The total number of samples sequenced is 63.