Nuclear Receptor-Dependent Bile Acid Signaling Is Required for Normal Liver Regeneration

Abstract

Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.

The role of bile salts in liver regeneration

“…Although a bile salt overload can trigger a proliferative response by causing hepatic injury, a cholic acid diet did not induce substantial toxic effects with a subsequent regenerative response. A moderate bile salt overload thus appears to act as a regenerative trigger per se [1,26,27]. Dietary bile salt-supplementation also accelerated liver regeneration after PHx, an effect that depended on the presence of Fxr [26].…”

“…A moderate bile salt overload thus appears to act as a regenerative trigger per se [1,26,27]. Dietary bile salt-supplementation also accelerated liver regeneration after PHx, an effect that depended on the presence of Fxr [26]. Conversely, depletion of hepatic bile salts by a bile salt-sequestering resin resulted in impaired DNA synthesis and liver regrowth [26,28].…”

“…Dietary bile salt-supplementation also accelerated liver regeneration after PHx, an effect that depended on the presence of Fxr [26]. Conversely, depletion of hepatic bile salts by a bile salt-sequestering resin resulted in impaired DNA synthesis and liver regrowth [26,28]. In bile saltdeficient Cyp27a1 -/-mice, liver regeneration after PHx was impaired [29].…”

“…In a pioneering study of Huang et al it was demonstrated that bile salt feeding (viz. cholic acid, a hydrophilic bile salt) induced hepatomegaly in mice with an intact and non-injured liver [26]. Although a bile salt overload can trigger a proliferative response by causing hepatic injury, a cholic acid diet did not induce substantial toxic effects with a subsequent regenerative response.…”

“…Bile salt signaling has emerged as an important player in liver regeneration after liver resection [26]. In a pioneering study of Huang et al it was demonstrated that bile salt feeding (viz.…”