Conditional Deletion of β-Catenin Reveals Its Role in Liver Growth and Regeneration

Tan, Xinping; Behari, Jaideep; Cieply, Benjamin; Michalopoulos, George K.; Monga, Satdarshan P.

doi:10.1053/j.gastro.2006.08.042

Cited by 327 publications

(482 citation statements)

References 45 publications

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“…Similar to β‐catenin‐LKO and LRP5‐6‐LDKO, we observed a significantly lower liver weight to body weight ratio in EC‐Wls‐KO6, 7, 14 (Fig. 2A).…”

Section: Resultssupporting

confidence: 67%

“…For quantification, hepatocytes with mitotic figures were counted in three to five random 200 × fields from three livers from each group at 24, 40, and 72 hours. For immunohistochemistry (IHC), paraffin sections were processed as described 6, 7. Antibody dilutions are listed in http://onlinelibrary.wiley.com/doi/10.1002/hep4.1196/full.…”

Section: Methodsmentioning

confidence: 99%

“…Mice with liver‐specific β‐catenin knockout (β‐catenin‐LKO) have been instrumental in discerning its many roles in hepatic physiology. These mice showed absence of pericentral gene expression validating pathway target genes, such as glutamine synthetase (GS), cytochrome P450 2E1 (Cyp2e1), and Cyp1a2 3, 4, 5, 6. A follow‐up study showed that dual KO of Wnt coreceptors LRP5 and LRP6 in the liver (LRP5‐6‐LDKO) also led to absent metabolic zonation 7.…”

mentioning

confidence: 99%

“…Additionally, β‐catenin has been shown to play an important role in liver regeneration (LR) after partial hepatectomy (PH), a tightly regulated process requiring precise cellular communication and spatiotemporal signaling 9. β‐Catenin‐LKO has delayed LR until 72 hours 6, 10. This was due to inadequate up‐regulation of β‐catenin target cyclin‐D1, which is critical for the G1‐ to S‐phase transition of hepatocytes 6, 11.…”

mentioning

confidence: 99%

“…β‐Catenin‐LKO has delayed LR until 72 hours 6, 10. This was due to inadequate up‐regulation of β‐catenin target cyclin‐D1, which is critical for the G1‐ to S‐phase transition of hepatocytes 6, 11. Regulation of cyclin‐D1 by β‐catenin during the LR process has been independently validated 12.…”

mentioning

confidence: 99%

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Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

Preziosi

Okabe

Poddar

et al. 2018

Hepatology Communications

109

156

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β‐Catenin in hepatocytes, under the control of Wnts, regulates pericentral gene expression. It also contributes to liver regeneration (LR) after partial hepatectomy (PH) by regulating cyclin‐D1 gene expression as shown in the β‐catenin and Wnt coreceptors low‐density lipoprotein receptor‐related protein 5/6 conditional knockouts (KO). However, conditional deletion of Wntless (Wls), required for Wnt secretion, in hepatocytes, cholangiocytes, or macrophages lacked any impact on zonation, while Wls deletion in macrophages only marginally affected LR. Here, we address the contribution of hepatic endothelial cells (ECs) in zonation and LR by characterizing EC‐Wls‐KO generated by interbreeding Wls‐floxed and lymphatic vessel endothelial hyaluronan receptor (Lyve1)‐cre mice. These mice were also used to study LR after PH. While Lyve1 expression in adult liver is limited to sinusoidal ECs only, Lyve1‐cre mice bred to ROSA26‐Stopflox/flox‐enhanced yellow fluorescent protein (EYFP) mice showed EYFP labeling in sinusoidal and central vein ECs. EC‐Wls‐KO mice showed decreased liver weights; lacked glutamine synthetase, cytochrome P450 2e1, and cytochrome P450 1a2; and were resistant to acetaminophen‐induced liver injury. After PH, EC‐Wls‐KO showed quantitative and qualitative differences in cyclin‐D1 expression at 24‐72 hours, which led to a lower hepatocyte proliferation at 40 hours but a rebound increase by 72 hours. ECs and macrophages isolated from regenerating livers at 12 hours showed significant up‐regulation of Wnt2 and Wnt9b messenger RNA; these are the same two Wnts involved in baseline β‐catenin activity in pericentral hepatocytes. Conclusion: At baseline, ECs secrete Wnt proteins essential for β‐catenin activation in pericentral hepatocytes. During LR, sinusoidal and central vein ECs and secondarily macrophages secrete Wnt2, while predominantly central vein ECs and secondarily macrophages are the likely source of Wnt9b. This process spatiotemporally regulates β‐catenin activation in hepatocytes to induce cell proliferation. (Hepatology Communications 2018;2:845‐860)

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“…Similar to β‐catenin‐LKO and LRP5‐6‐LDKO, we observed a significantly lower liver weight to body weight ratio in EC‐Wls‐KO6, 7, 14 (Fig. 2A).…”

Section: Resultssupporting

confidence: 67%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

Preziosi

Okabe

Poddar

et al. 2018

Hepatology Communications

109

156

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Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract

et al. 2018

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The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.

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Restoring Tissue Homeostasis

Özhan

Weidinger

2014

WNT Signaling in Development and Disease

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Conditional Deletion of β-Catenin Reveals Its Role in Liver Growth and Regeneration

Cited by 327 publications

References 45 publications

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract

Restoring Tissue Homeostasis

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