The role of bile salts in liver regeneration

Abstract

A growing body of evidence has demonstrated that bile salts are important for liver regeneration following partial hepatectomy. The relative bile salt overload after partial liver resection causes activation of bile salt receptors in non-parenchymal (viz. the plasma membrane receptor TGR5) and parenchymal (viz. the intracellular receptor FXR) cells in the liver, thus, providing signals to the regenerative process. Impaired bile salt signaling in mice with genetic deficiency of Tgr5 or Fxr results in delayed liver regeneration after partial hepatectomy, and is accompanied by mortality in case of Fxr knock-out mice. Conversely, compensatory liver re-growth in hepatectomized mice can be stimulated by feeding of bile salts or alisol B 23-acetate, a natural triterpenoid agonist of Fxr. A large number of animal studies underscore the importance of strict maintenance of bile salt homeostasis for proper progression of liver regeneration. Both ileal and hepatic Fxr play a key role in regulation of bile salt homeostasis and, thus, preventing hepatotoxicity caused by excessive levels of bile salts. They further contribute to liver regeneration by induction of mitogenic factors. Agents that target bile salt receptors hold promise as drugs to stimulate liver regeneration in selected patients.

Keywords: Bile salt homeostasis; Bile salt signaling; Farnesoid X receptor; Liver regeneration; Liver surgery.

Fig. 1

Emerging roles of bile salts in liver regeneration after partial hepatectomy. Circulating and hepatic levels of bile salts rise shortly after PHx. This causes activation of bile salt receptors at the cell surface of Kupffer cells (TGR5) and inside the hepatocyte (FXR). Kupffer cells release soluble factors that prime cell cycle re-entry of quiescent hepatocytes. FXR regulates cell cycle progression through induction of Foxm1b, and through the ileal FXR/FGF19/FGFR4 signaling axis. Bile salt levels in the hepatocyte need to be tightly controlled to prevent toxicity. Excessive bile salt levels result in mitochondrial damage and release of reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) that can trigger activation of nearby Kupffer cells. An exaggerated inflammatory response of Kupffer cells results in apoptosis and necrosis of hepatocytes. Slightly elevated bile salt levels may stimulate cellular antioxidant defense responses and precondition the liver. FXR and signaling via FGF19/FGFR4/βKlotho play an important role in bile salt homeostasis, amongst others by exerting negative feedback control of bile salt synthesis. The composition, and hence the signaling properties, of the circulating bile salt pool is determined by the gut flora. The influence of the gut microbiome on liver regeneration after PHx is being explored