. 2018 May 28;4(1):1-46.

doi: 10.18053/jctres.04.201801.001. Epub 2018 Feb 16.

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

Lianne de Haan¹, Sarah J van der Lely¹, Anne-Loes K Warps¹, Quincy Hofsink¹, Pim B Olthof¹, Mark J de Keijzer¹, Daniël A Lionarons², Lionel Mendes-Dias¹, Bote G Bruinsma^{1

3

4}, Korkut Uygun^{3

4}, Hartmut Jaeschke⁵, Geoffrey C Farrell⁶, Narci Teoh⁶, Rowan F van Golen¹, Tiangang Li⁵, Michal Heger^{1

7}

Affiliations

¹ Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
² Oncogene Biology Laboratory, Francis Crick Institute, London, United Kingdom.
³ Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁴ Shriners Hospitals for Children, Boston, MA, United States.
⁵ Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS, United States.
⁶ Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
⁷ Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Institute of Biomembranes, Utrecht University, Utrecht, the Netherlands.

PMID: 30761355
PMCID: PMC6370335
DOI: 10.18053/jctres.04.201801.001

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

Lianne de Haan et al. J Clin Transl Res. 2018.

. 2018 May 28;4(1):1-46.

doi: 10.18053/jctres.04.201801.001. Epub 2018 Feb 16.

Authors

Affiliations

¹ Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
² Oncogene Biology Laboratory, Francis Crick Institute, London, United Kingdom.
³ Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁴ Shriners Hospitals for Children, Boston, MA, United States.
⁵ Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS, United States.
⁶ Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
⁷ Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Institute of Biomembranes, Utrecht University, Utrecht, the Netherlands.

PMID: 30761355
PMCID: PMC6370335
DOI: 10.18053/jctres.04.201801.001

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.

Keywords: arnesoid X receptor enteral; detoxification; fibroblast growth factor; hepatocyte proliferation; mitotic signaling; surgery; transport and canalicular excretion.

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Figures

Figure 1.. Changes in hepatic hemodynamics that lead to liver regeneration. Three physiological changes following PHx trigger liver regeneration. Altered hepatic hemodynamics (1) lead to increased hepatic exposure to pro-regenerative factors originating from the portal circulation. Additionally, platelets accumulate in the space of Disse and release pro-regenerative molecules. The hepatocellular redox state (2) shifts to a pro-oxidative state due to ischemia/reperfusion, cholestasis, and bile acid overload. NRF-2 and other redox-active enzymes upregulate pro-oxidant enzymes and downregulates antioxidant enzymes, leading to increased levels of H2O2, which promotes cell proliferation through both ERK-cyclin D1-p-RB and Notch signaling. PHx induces hepatocyte proliferation through an immune response (3), resulting from endotoxemia, intestine-derived PAMPs, and damaged cells leaking DAMPs. PAMPs and DAMPs bind PRRs on Kupffer cells, triggering the release of cytokines such as TNF-α and IL-6. Complement factors C3a and C5a are also triggered by the immune response and activate TNF-α and IL-6 release through complement receptors. Abbreviations: SEC, sinusoidal endothelial cell; BA, bile acid; NRF-2, nuclear factor (erythroid-derived 2)-like 2; H2O2, hydrogen peroxide; ERK, extracellular signal-regulated kinase; pRB, phosphorylated retinoblastoma protein; DAMPs, damage-associated molecular patterns; PRR, pattern recognition receptor; PAMPs, pathogen-associated molecular patterns; IL-6, interleukin 6; TNF-α, tumor necrosis factor alpha.

Figure 2.. Intercellular and intracellular signals that initiate liver regeneration. Three mechanisms lead to hepatocyte proliferation. In response to complement factors C3a, C5a, PAMPs, and DAMPs, Kupffer cells release TNF-α, IL-6, PGE2, and IL-1β. TNF-α induces an autocrine loop through NF-κB production by B-cells. IL-6, PGE2, and IL-1β bind their cognate receptors on hepatocytes (A). Platelets accumulate in the space of Disse and release an armament of growth factors, including HGF, from their α-granules. Pro-HGF is released from SECs and HSCs and is converted to HGF by uPA, which is activated as a result of ECM damage after PHx. Platelets also release serotonin, which stimulates SECs, and sphringosine-1-phosphate to stimulate IL-6 release (B). PGE2 and IL-1β coming from Kupffer cells stimulate amphiregulin production in hepatocytes. HGF binds its receptor c-Met and activates hepatocyte proliferation through ERK-1/2 MAPK. IL-6 binds the IL-6 receptor and activates JAK, which induces hepatocyte proliferation through STAT3 and through the RAS-ERK-1/2 MAPK pathway. EGF, TGF-α, HBEGF, and amphiregulin enhance the effect of HGF through EGFR2. EGF is produced in the duodenum and reaches the liver through the portal circulation. TGF-α is produced by proliferating hepatocytes. HBEGF is released from monocytes and macrophages and converted to its active form by metalloproteinases. TNF-α (from Kupffer cells) and ROS enhance the UPR that is mediated by IRE1α. The UPR inhibits ER stress that in turn activates COX-2 expression. COX-2 is also stimulated by ROS, PAMPs, and DAMPs. Enhanced COX-2 expression increases C/EBPβ and C/EBPδ expression and decreases C/EBPα expression, thereby stimulating hepatocyte proliferation (C). Abbreviations: DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; IL-1β, interleukin 1β; IL-6, interleukin 6; TNF-α, tumor necrosis factor alpha; SEC, sinusoidal endothelial cell; HSC, hepatic stellate cell; HGF, hepatocyte growth factor; uPA, urokinase plasminogen activator; C/EBPα, β, and δ, CCAAT enhancer binding protein alpha, beta, and delta; TGF-α, tumor growth factor alpha; EGF, epidermal growth factor; EGFR2, epidermal growth factor receptor 2; JAK, Janus kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; STAT3, signal transducer and activator of transcription 3; IRE1α, inositol-requiring enzyme-1α; UPR, unfolded protein response; ROS, reactive oxygen species.

**Figure 3.**
**Non-exhaustive list of bile acid species and bile acid analogues, chemical properties, and toxicity**. LogP (octanol:water partition coefficient) values were retrieved from PubChem and were predicted with XLogP2 or XLogP3 software. The 50% lethal concentration (LC50, used for in vitro data) and 50% lethal dose (LD50, used for in vivo data) were obtained from the material safety data sheets (retrieved from the Cayman Chemicals and Spectrum Chemical website) and the Toxicological Data Network (TOXNET, https://toxnet.nlm.nih.gov/) as well as available literature [544] [544]. Abbreviations (bile acids excluded): NA: information not available; iv: intravenous; ip: intraperitoneal; MW: molecular weight; sc: subcutaneous; TDLO; the lowest dose causing a toxic effect. Abbreviations (bile acids): 12-keto-LCA: 12-ketolithocholic acid / 12-oxolithocholic acid; 12-oxo-CDCA: 12-oxochenodeoxycholate / 12-oxochenodeoxycholic acid; 3,7-DiHCA : 3,7-dihydroxy-5-cholestenoic acid; 3,7-diketo-CA : 3,7-diketocholanic acid / 3,7-dioxhocholanoic acid; 3-keto-CA: 3-ketocholic acid / 3-oxocholic acid; 3-keto-LCA: 3-ketolithocholic acid / dehydrolithocholic acid; 3-SCDCA: chenodeoxycholic acid 3-sulfate; 3-S-GCDCA: glycochenodeoxycholic acid 3-sulfate; 3S-TLCA: taurolitocholate sulfate / taurolithocholic acid 3-sulfate; 3-sulfate CA: cholic acid 3-sulfate; 5-THCA: trihydrocoprostanic acid / (3alpha,5beta,7alpha,12alpha)-3,7,12-trihydroxycholestane-5-carboxylic acid; 6-keto-LCA: 6- ketolithocholicacid;7-Hoca: 7α-hydroxy-3-oxo-4-cholestenoicacid;7-keto-DCA:7-ketodeoxycholicacid;7-keto-LCA:7- ketolithocholic acid / nutriacholic acid; 7-SCDCA: chenodeoxycholic acid 7-sulfate; 7-S-GCDCA: glycochenodeoxycholic acid 7- sulfate; 7-sulfate CA: cholic acid 7-sulfate; α-MCA: α-muricholate / α-muricholic acid / α-hyocholic acid; α-PCCA: α-phocaecholate / alpha-phocaecholic acid; β-MCA: β-muricholate / β-muricholic acid / β-hyocholic acid; β-PCCA: β-phocaecholate / phocaecholic acid; ω-MCA: ω-muricholate / ω-muricholic acid / ω-hyocholic acid; ACA: allocholate / allocholic acid; AlloAVCA: alloavicholate / alloavicholic acid; AlloCDCA: allochenodeoxycholate / allochenodeoxycholic acid; AlloDCA: allodeoxycholate / allodeoxycholic acid; AlloLCA: allolithocholic acid; AlloUDCA: alloursodeoxycholic acid; ApoCA: apocholate / apocholic acid; AVCA: avicholate / avicholic acid; AVDCA: avideoxycholate / avideoxycholic acid; BCA: bitocholate / bitocholic acid; CA: cholate / cholic acid; CCA: ciliatocholate / ciliatocholic acid; CDCA: chenodeoxycholate / chenodeoxycholic acid; CGA: cygnocholate / cygnocholic acid; CSA: cholestenoic acid; DCA: deoxycholate / deoxycholic acid; DHA: dehydrocholate / dehydrocholic acid; DiHCA: dihydroxycoprostanoic acid; DinorCA: dinorcholic acid; DinorCDCA: dinorchenodeoxycholic acid; DinorDCA: dinordeoxycholic acid; DinorHDCA: dinorhyodeoxycholic acid; DinorLCA: dinorlithocholic acid; DinorUDCA: dinorursodeoxycholic acid; GCA: glycocholate / glycocholic acid; GCDCA: glycochenodeoxycholate / glycochenodeoxycholic acid; GDCA: glycodeoxycholate / glycodeoxycholic acid; GHCA: glycohyocholate / glycohyocholic acid; GHDCA: glycohyodeoxycholate / glycohyodeoxycholic acid; GLCA: glycolithocholate / glycolithocholic acid; GLCA-3-S: glycolithocholate 3-sulfate / glycolithocholic acid 3-sulfate; Glyco-OCA: glyco-obeticholic acid; GUCA: glycoursocholate / glycoursocholic acid; GUDCA: glycoursodeoxycholate / glycoursodeoxycholic acid; HCA: hemulcholate / hemulcholic acid; HDCA: hyodeoxycholic acid / murideoxycholic acid; LagoDCA: lagodeoxycholic acid; LCA: lithocholate / lithocholic acid; NorCA: norcholate / norcholic acid; NorCDCA: norchenodeoxycholic acid; NorDCA: nordeoxycholic acid; NorHDCA: norhyodeoxycholic acid; NorLCA: norlithocholic acid; NorUCA: noruroscholic acid; NorUDCA: norursodeoxycholic acid; OCA: obeticholic acid / ocaliva / 6-ethylchenodeoxycholic acid / INT-747; PCA: pythocholic acid; S-LCA: lithocholic acid 3-sulfate; T-alpha-MC: tauro-α-muricholic acid; T-beta-MC: tauro-β-muricholic acid; TCA: taurocholate / taurocholic acid; TCA-3-S: taurocholate 3-sulfate / taurocholic acid 3-sulfate; TCDCA: taurochenodeoxycholate / taurochenodeoxycholic acid; TCDCA3S: taurochenodeoxycholic acid 3-sulfate; TCDCA7S: taurochenodeoxycholic acid 7-sulfate; TDC(A): taurodeoxycholate / taurodeoxycholic acid; THCA: trihydrocoprostanic acid / coprocholic acid / 3,7,12-trihydroxycholestan-26-oic acid; THDCA: taurohyodeoxycholate / taurohyodeoxycholic acid; TLCA: taurolithocholate / taurolithocholic acid; TUCA: tauroursocholate / tauroursocholic acid; TUDCA: tauroursodeoxycholate / tauroursodeoxycholic acid; UA: ursolic acid; UCA: ursocholic acid; UClA: ursocholanic acid; UDCA: ursodeoxycholate / ursodeoxycholic acid; VA: varanic acid; VCA: vulpecholate / vulpecholic acid.

Figure 4.. **Hepatocellular bile acid transporters**. Basolateral import of bile acids is mediated by NTCP (Na⁺-dependent) and OATP isoforms (Na+-independent). Bile acids are exported through the basolateral exporters MRP3, MRP4, and the OSTα and OSTβ heterodimer and through the canalicular exporters BSEP, MRP2, and possibly MDR1. Bile acids regulate their own efflux through hepatic farnesoid X receptor (hFXR). Bile acid-activated hFXR induces the OSTα and OSTβ heterodimer and MRP2 and, as heterodimer with RXR, BSEP. hFXR also activates SHP that inhibits the importers NTCP, the OSTα and OSTβ heterodimer, LXR, and LRH-1. LXR and LRH-1 normally inhibit CYP7A1, CYP8B1, and CYP27A1, but because of SHP activation by hFXR and consequent inhibition of LRH-1 and LXR, bile acids are synthesized from cholesterol. Additionally, LRH-1 normally stimulates the expression of BSEP and the OSTα and OSTβ heterodimer, while induction of SHP by hFXR results in inhibition of those exporters. Abbreviations: BA, bile acid; BSEP, bile salt export pump; CAR, constitutively active/androstane receptor; CYP, cytochrome p450; hFXR, hepatic farnesoid X receptor; LRH-1, liver receptor homolog 1; LXR, liver X receptor; MDR1, multidrug resistance associated protein 1; MRP3/4, multidrug resistance protein 3 and 4; NTCP, Na+-taurocholate co-transporting polypeptide; OATP, organic anion transporting polypeptide; OSTα/β, organic solute transporter alpha/beta; PXR, pregnane X receptor; RXR, retinoid X receptor; SHP, small heterodimer partner.

**Figure 5.. Chronological flowchart of mitogenic signaling by bile acids.**

Figure 6. Hepatocyte-enterocyte interplay after PHx. Bile acids are taken up in the intestine by the enteral importer ASBT and exported into the portal circulation by the OSTα and OSTβ heterodimer and MRP3. In the enterocyte, bile acids activate eFXR that activates the OSTα and OSTβ heterodimer and induces the transcription of FGF15/19. FGF15/19 binds to the FGFR4/β-klotho receptor complex that in turn stimulates mitosis through pathways involving hFXR/FOXM1B, JAK/STAT3/FOXM1B, MAPK, and NF-κB. In the hepatocyte, bile acids can bind PXR and hFXR that stimulate mitosis through STAT3 and FOXM1B, respectively. Bile acids bound to RXR complexed with PPAR-α can also induce hepatocyte proliferation. Abbreviations: BA, bile acid; ASBT, apical sodium dependent bile acid transporter; FGF15/19, fibroblast growth factor 15/19; eFXR, enteral farnesoid X receptor; LRH-1, liver receptor homolog 1; OSTα/β, organic solute transporter alpha/beta; MRP3, multidrug resistance protein 3; FGFR4, fibroblast growth factor receptor 4; JAK, Janus kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; STAT3, signal transducer and activator of transcription; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; FOXM1B, forkhead box M1B; hFXR, hepatic farnesoid X receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; PPAR-α, peroxisome proliferator-activated receptor alpha.

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

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

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