Activation of Inactive Hepatocytes through Histone Acetylation

The mechanisms by which hepatic function is maintained after extensive parenchymal loss are unclear. In this study, we propose a novel concept of “functional heterogeneity” of hepatocytes based on their different expression of acetylated histones, the markers of active gene transcription, to explain the powerful compensatory capability of the liver. In the healthy human liver, only a fraction of the hepatocytes were marked by acetylated histones (ac-H2AK5, ac-H2BK5, ac-H3K9, ac-H3K14, ac-H3K27, and ac-H3K9/14). With the progression of cirrhosis, the ratio of the positive cells was gradually elevated, accompanied by the gradual exhaustion of the negative cells. By examining the global transcriptome of the mouse hepatocytes, we observed that the primed genes in the positive cells were much more numerous than those in negative cells. In a 70% hepatectomized mouse, the remnant hepatocytes were extensively activated, and the liver function was well maintained even when regeneration was severely inhibited. The functional compensation was absolutely dependent on the elevated expression of acetyl-histones. Additionally, when liver regeneration was blocked, the metabolism-related genes seemed to be preferentially transcribed. In conclusion, we demonstrate that normally, part of the active hepatocytes are competent for routine physiological requirements. The inactive hepatocytes, delicately regulated by acetyl-histones, act as a functional reservoir for future activation to restore the liver function after massive parenchymal loss.