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Mol Cell Biol. 2018 Dec 17. pii: MCB.00405-18. doi: 10.1128/MCB.00405-18. [Epub ahead of print]

Rapid recapitulation of non-alcoholic steatohepatitis upon loss of HCF-1 function in mice.

Author information

1
Center for Integrative Genomics, Génopode, University of Lausanne, CH-1015 Lausanne, Switzerland.
2
Swiss Institute of Bioinformatics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
3
Center for Integrative Genomics, Génopode, University of Lausanne, CH-1015 Lausanne, Switzerland winship.herr@unil.ch.

Abstract

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.

PMID:
30559308
DOI:
10.1128/MCB.00405-18
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