Rapid Recapitulation of Nonalcoholic Steatohepatitis upon Loss of Host Cell Factor 1 Function in Mouse Hepatocytes

ABSTRACT

Host cell factor 1 (HCF-1), encoded by the ubiquitously expressed X-linked gene Hcfc1, is an epigenetic coregulator important for mouse development and cell proliferation, including during liver regeneration. We used a hepatocyte-specific inducible Hcfc1 knockout allele (called Hcfc1^hepKO) to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1^hepKO/Y males by 4 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- to 24-day terminal nonalcoholic fatty liver (NAFL), followed by nonalcoholic 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 nontranscriptional roles. These genetically engineered loss-of-HCF-1 mice can be used to study NASH as well as NAFLD resolution.

KEYWORDS:

• HCF-1
• Hcfc1
• NAFLD
• NASH
• PGC1alpha
• chromatin
• gene expression
• steatosis

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Correction for Minocha et al., “Rapid Recapitulation of Nonalcoholic Steatohepatitis upon Loss of Host Cell Factor 1 Function in Mouse Hepatocytes”

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00405-18.

ACKNOWLEDGMENTS

We thank Damien De Bellis, Bruno Humbel, and the Electron Microscopy Facility (University of Lausanne) for help with electron microscopy; Frederic Preitner and the Mouse Metabolic Facility (University of Lausanne) for help with AST and carbohydrate metabolism tests; Vera Lemos, Johan Auwerx, and the Metabolic Facility (EPFL) for help with assessment of triglycerides and cholesterol levels; the Cellular Imaging Facility of the University of Lausanne Faculty of Biology and Medicine for microscope access; Keith Harshman and the Genomic Technologies Facility of the University of Lausanne for ChIP-Seq and RNA-Seq analyses; Biocrates Life Sciences AG, Austria, for metabolomic tests; and Fisun Hamaratoglu for comments on the manuscript.

We have no conflicts of interest to declare.

This research was supported by Swiss National Science Foundation grants CRSII3_160798 and 31003A_170150 and by the University of Lausanne.

S.M. and W.H. conceived and designed experiments. S.M., D.V., C.M., M.L., and D.P. performed the experiments. S.M., V.P., L.R., N.G., and W.H. analyzed the data. S.M. and W.H. wrote the paper. All authors participated in the discussion of the data and in production of the final version of the manuscript.