Elongation of very long chain fatty acids-3 () is activated by ZHX2 and is a regulator of cell cycle progression.

Zinc fingers and homeoboxes 2 () are transcriptional regulators of liver gene expression with key functions in embryonic development as well as tissue regeneration in response to damage and disease, presumably through its control of target genes. Previous microarray data suggested that elongation of very long chain fatty acids-3 (), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids that are often dysregulated in diseases and regulate key cellular processes including proliferation. Since several previously identified targets become dysregulated in liver damage, we investigated the relationship between and in liver development, damage, and regeneration. Here, using mouse and cell models, we demonstrate that positively regulates expression in the liver and that male-biased hepatic expression is established between 4 and 8 wk of age in mice. is dramatically repressed in mouse models of liver regeneration, and the reduced levels in the regenerating liver are associated with changes in hepatic VLCFAs. Human hepatoma cell lines with forced expression have lower rates of cell growth; analysis of synchronized cells indicates that this reduced proliferation correlates with cells stalling in S-phase and lower mRNA levels of cell cyclins. Taken together, these data indicate that expression helps regulate cellular proliferation during liver development and regeneration, possibly through control of VLCFAs. Numerous targets of the transcription factor are dysregulated in liver disease. We show that the elongase is a novel target. and expression change during liver regeneration, which is associated with changes in very long chain fatty acids. Forced expression reduces cell growth and blocks cell cycle progression. This suggests that may account, at least in part, for the relationship between and proliferation during liver development and disease.