The liver is the most regenerative organ in mammals, capable of regrowing lost sections, albeit imperfectly in comparison to the capabilities of highly regenerative species such as salamanders. Researchers here demonstrate that the sex hormone estradiol is involved in the regulation of liver regeneration, and that regeneration can be accelerated via artificially increased levels of estradiol. This is particularly interesting in the context of recent work showing that loss of estradiol with aging is involved in loss of muscle mass, due to effects on stem cell activity. One might wonder if this sort of mechanism will show up in other tissues as well.

The endogenous hormone estradiol is widely recognized as a stress signaling molecule. It is mainly produced by the ovary, and its production can be induced under certain contexts and stimuli such as during the estrus cycle and in late pregnancy. Estradiol exerts its multiple functions by binding to GPR30, estrogen receptor (ER) α, or ERβ, which are members of the nuclear receptor super family.

Estradiol production is also induced after liver resection/injury, suggesting this hormone plays a role in liver regeneration. Several genes that participate in liver regeneration have been identified, including those encoding the inflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6). In particular, we have previously focused on the molecules essential for triggering liver regeneration after partial hepatectomy (PH) using mouse models. In addition to these cytokines, the production of the chemical hormone estradiol is also induced in the acute phase of liver injury after PH, via the ovary and testes.

We have further demonstrated that estrogen induces hepatocyte proliferation after PH, which was delayed by ovariectomy. This estradiol induction after PH was in turn found to induce ERα expression in the mainly periportal hepatocytes. Moreover, the WT mice showed transient steatosis during liver regeneration after PH. Therefore, we hypothesized that PH initially triggers estradiol production, leading to elevated ERα expression, to consequently initiate the processes of β-oxidation enzyme expression for anti-steatosis.

In the present study, we tested this hypothesis by analyzing the liver regeneration process in ERα knockout (KO) mice compared with that in their wild-type (WT) littermates. Estradiol administration accelerated liver regeneration through ERα, indicating the feasibility of the estrogen-ERα axis as a target. These findings establish the foundation for the therapeutic application of estradiol to accelerate liver regeneration after resection in clinical settings.