Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis

Abstract

Background: Liver regeneration following partial hepatectomy (PHx) is a complicated process involving multiple organs and several types of signaling networks. The bile acid-activated metabolic pathways occupy an auxiliary yet important chapter in the entire biochemical story. PHx is characterized by rapid but transient bile acid overload in the liver, which constitutes the first wave of proliferative signaling in the remnant hepatocytes. Bile acids trigger hepatocyte proliferation through activation of several nuclear receptors. Following biliary passage into the intestines, enterocytes reabsorb the bile acids, which results in the activation of farnesoid X receptor (FXR), the consequent excretion of fibroblast growth factor (FGF)19/FGF15, and its release into the enterohepatic circulation. FGF19/FGF15 subsequently binds to its cognate receptor, fibroblast growth factor receptor 4 (FGFR4) complexed with β-klotho, on the hepatocyte membrane, which initiates the second wave of proliferative signaling. Because some bile acids are toxic, the remnant hepatocytes must resolve the potentially detrimental state of bile acid excess. Therefore, the hepatocytes orchestrate a bile acid detoxification and elimination response as a protective mechanism in concurrence with the proliferative signaling. The response in part results in the excretion of (biotransformed) bile acids into the canalicular system, causing the bile acids to end up in the intestines. Relevance for patients: Recently, FXR agonists have been shown to promote regeneration via the gut-liver axis. This type of pharmacological intervention may prove beneficial for patients with hepatobiliary tumors undergoing PHx. In light of these developments, the review provides an in-depth account of the pathways that underlie post-PHx liver regeneration in the context of bile acid homeostasis in the liver and the gut-liver signaling axis.

Finding fibroblast growth factor 19 during cholestasis: Does x mark the spot?

“…Plasma FGF19 and hepatic FGF19 mRNA levels are elevated in patients with extrahepatic cholestasis, with a decrease in systemic and hepatic FGF19 following biliary drainage. 1 Indeed, we found a robust increase in hepatic FGF19 expression, while positive staining was confined to the cytoplasm of predominantly cholangiocytes and ductular cells from smaller ductules (likely progenitor cells) in patients with alcoholic hepatitis. 2 Gallbladder epithelial cells from a resected gall bladder served as appropriate positive staining control, 3 while non-neoplastic liver with portal tracts was negative for FGF19 protein, 3,4 although large caliber bile ducts showed weak positive staining for FGF19.…”

“…Hepatocyte bile salt production is largely controlled by fibroblast growth factor 19 (FGF19), normally produced by ileal enterocytes in response to activation of the intestinal bile salt receptor FXR. 1 Enterohepatic cycling of FGF19 prevents hepatic bile salt toxicity by downregulating hepatocyte bile salt production by CYP7A1. Although undetectable in native livers, the compensatory induction of hepatic FGF19 expression has been noted in patients with extrahepatic cholestasis.…”

Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid

“…In addition, the liver has the capacity to regenerate. After hepatic injury or surgical resection, the liver rapidly regenerates to a predefined liver:body weight ratio to balance its metabolic function [ 1 ]. This equilibration to a preset ideal liver size is often referred to as the “hepatostat” [ 2 ].…”

“…Considering the high mortality rate, recent studies have investigated pharmacological modulation of liver regeneration to augment future remnant liver size [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. In this context, an important role has been ascribed to BAs and drugs that activate BA receptors, most notably the farnesoid X receptor (FXR) [ 1 , 22 , 23 , 24 ]. BAs can directly (through hepatic FXR) and indirectly (through intestinal FXR and the subsequent induction and portal release of fibroblast growth factor (FGF)15/19 (rat/human orthologue)) trigger hepatocyte proliferation via the portal circulation [ 22 ].…”

“…BAs can directly (through hepatic FXR) and indirectly (through intestinal FXR and the subsequent induction and portal release of fibroblast growth factor (FGF)15/19 (rat/human orthologue)) trigger hepatocyte proliferation via the portal circulation [ 22 ]. A detailed summary of the molecular pathways controlling BA signaling through FXR has been recently published [ 1 ]. Obeticholic acid (OCA) is a synthetic, potent, and selective FXR agonist that is already approved for reducing cholestasis in patients with primary biliary cholangitis (PBC) [ 25 , 26 ].…”