Fibroblast Growth Factor 15–Dependent and Bile Acid–Independent Promotion of Liver Regeneration in Mice

Kong, Bo; Sun, Runbin; Huang, Mingxing; Chow, Monica D.; Zhong, Xiao‐bo; Xie, Wen; Lee, Yi‐Horng; Guo, Grace L.

doi:10.1002/hep.30041

Cited by 41 publications

(39 citation statements)

References 42 publications

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“…The Fgf15 –/– mice were raised with a 75%/25% mixed C57BL/6J/A129 background, respectively, because in a C57BL/6J background, knockout was embryonically lethal. TG mice were generated with a C57BL/6J background . At 8‐10 weeks of age, mice were fed either a control chow diet, 0.2% cholic acid (CA)‐containing diet (Cat.…”

Section: Methodsmentioning

confidence: 99%

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Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Schumacher

Kong

et al. 2019

Hepatology

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Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15–/– mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15–/– mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4‐induced LF model in wild type (WT), Fgf15–/–, and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine‐ or cholic acid–containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15–/– mice; and (3) treatment of a human HSC line, LX‐2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15–/– mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15–/– mice. HSCs from Fgf15–/– mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX‐2 cells, FXR activation increased peroxisome proliferator‐activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c‐Jun N‐terminal kinase pathways and reduced nuclear factor kappa‐light‐chain‐enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.

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Section: Methodsmentioning

confidence: 99%

“…TG mice were generated with a C57BL/6J background. (22) At 8-10 weeks of age, mice were fed either a control chow diet, 0.2% cholic acid (CA)-containing diet (Cat. # C1129; Sigma-Aldrich, St. Louis, MO), or a 2% cholestyramine-containing diet (Cat.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Schumacher

Kong

et al. 2019

Hepatology

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“…Also, in the ileum enterocyte, BA‐induced FXR‐dependent FGF15 induction has been identified as an important regulator of liver homeostasis, 44 regeneration after PH 45,46 and alcohol‐related liver injury 47 . Direct positive impact on hepatocyte (and cholangiocyte) cell cycle progression, 45,48 and indirect regulation through BA synthesis suppression 45 by FGF15 have been reported, although more complex effects of FGF15 appear to be involved in relation to NASH and fibrosis 49 . Thus, FXR‐dependent adaptive responses are crucial to protect the repairing liver after injury and to boost regenerative responses.…”

Section: Tgr5‐dependent Protective Responses Against Ba Overloadmentioning

confidence: 99%

Hepatoprotective impact of the bile acid receptor TGR5

Merlen

Bidault

Kahale

et al. 2020

Liver International

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During liver repair after injury, bile secretion has to be tightly modulated in order to preserve liver parenchyma from bile acid (BA)-induced injury. The mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides their historical role in lipid digestion, bile acids (BA) and their receptors constitute a signalling network with multiple impacts on liver repair, both stimulating regeneration and protecting the liver from BA overload. BA signal through nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors to elicit a wide array of biological responses. While a great number of studies have been dedicated to the hepato-protective impact of FXR signalling, TGR5 is by far less explored in this context. Because the liver has to face massive and potentially harmful BA overload after partial ablation or destruction, BA-induced protective responses crucially contribute to spare liver repair capacities. Based on the available literature, the TGR5 BA receptor protects the remnant liver and maintains biliary homeostasis, mainly through the control of inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity and sinusoidal blood flow. Mouse experimental models of liver injury reveal that in the lack of TGR5, excessive inflammation, leaky biliary epithelium and hydrophobic BA overload result in parenchymal insult and compromise optimal restoration of a functional liver mass. Translational perspectives are thus opened to target TGR5 with the aim of protecting the liver in the context of injury and BA overload. K E Y W O R D Sbile acids, bile acid pool, hepatoprotection, liver injury, paracellular permeability, TGR5 | B ILE ACIDS AND THE ENTEROHEPATI C C YCLEBile acids, the end products of cholesterol catabolism, are produced in hepatocytes and secreted in the canalicular lumen, flow through the bile ducts towards the duodenum, travel in the intestine until they are massively reabsorbed in the ileum back to the liver along the so-called enterohepatic cycle (EHC). The small BA fraction escaping from ileal reabsorption and flowing through the colon is then transformed by the gut microbiota, resulting in the production of secondary BA which are more hydrophobic -thus more toxic -than primary BA (those produced in hepatocytes). Hydrophobic secondary BA cross passively the colon epithelium and join the other BA

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“…FGF15 is secreted into portal circulation to function as a hormone [18]. In the liver, FGF15 can inhibit BA synthesis when binding to its receptor FGFR4, which is critical for BA homeostasis [19,20,21,22,23].…”

Section: Ileal Fxr Activation and Fgf15 Expression Was Upregulated Inmentioning

confidence: 99%

“…Animal experiments have shown that FGF15 is essential for hepatic homeostasis, and overexpression of FGF15/19 in the liver has beneficial effects on multiple liver diseases, including sclerosing cholangitis Page 20 of 30 [20], alcoholic fatty liver [22], and NAFLD [21,29]. In addition to its functions in hepatic metabolism, FGF15 has also been shown to contribute to liver regeneration [23,43,44]. In human, circulating FGF19 has been found to be increased in patients with biliary cirrhosis [45] and in patients with alcoholic hepatitis [46], which is accompanied with inhibition of BA synthesis.…”

Section: Gut Dysbiosis Can Be An Adaptive Response To Liver Injurymentioning

confidence: 99%

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

Yan

Khambu

Chen

et al. 2020

Preprint

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Objective:The gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury. Design:Fecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5 ∆hep mice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice.Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene, or given a fibroblast growth factor receptor 4 (FGFR4) inhibitor. Results:The composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria in Atg5 ∆hep mice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice. Conclusion:Gut dysbiosis can remedy liver injury in Atg5 ∆hep mice through the FXR-FGF15 signaling.Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gutliver axis.

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Fibroblast Growth Factor 15–Dependent and Bile Acid–Independent Promotion of Liver Regeneration in Mice

Cited by 41 publications

References 42 publications

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Hepatoprotective impact of the bile acid receptor TGR5

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

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