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. We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1 ^hepKO), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1 ^hepKO/Y males by four days. In heterozygous Hcfc1 ^hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1 ^hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. The livers with Hcfc1 ^hepKO/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 Hcfc1 ^hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1α protein, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1 ^hepKO/Y liver pathology. Thus, HCF-1 is essential for hepatocyte function, likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice can be used to study NASH as well as NAFLD resolution.