Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss

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• 作者：Christoph Tschuor¹ ; Ekaterina Kachaylo¹ ; Pë ; rparim Limani¹ ; Dimitri A. Raptis¹ ; Michael Linecker¹ ; Yinghua Tian¹ ; Uli Herrmann² ; Kamile Grabliauskaite¹ ; Achim Weber³ ; Amedeo Columbano⁴ ; Rolf Graf¹ ; Bostjan Humar¹ ; ^&dagger ; ; ^{bostjan.humar@usz.ch" class="auth_mail" title="E-mail the corresponding author} ; Pierre-Alain Clavien¹ ; ^&dagger ; ; ^{clavien@access.uzh.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CAR ; constitutive androstane receptor ; CITCO ; (6-(4-chlorophenyl)imidazo[2 ; 1-b][1 ; 3]thiazole-5-carbaldehydeO-(3 ; 4-dichlorobenzyl)oxime) ; eHx ; extended hepatectomy ; huCAR ; humanized CAR ; SFSS ; small-for-size syndrome ; sHx ; standard hepatectomy ; TCP ; 1 ; 4-bis(2-(3 ; 5-dichloropyridyloxy))benzene
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：65
• 期：1
• 页码：66-74
• 全文大小：3071 K

文摘

Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the small-for-size-syndrome (SFSS). The molecular processes underlying liver failure are ill-understood. Here, we explored the role and the clinical potential of Nr1i3 (constitutive androstane receptor, Car) in liver failure following hepatectomy.

Methods

Activators of Car, various hepatectomies, Car^−/− mice, humanized CAR mice, human tissue and ex vivo liver slice cultures were used to study Car in the SFSS. Pathways downstream of Car were investigated by in vivo siRNA knockdown.

Results

Excessive tissue loss causing liver failure is associated with deficient induction of Car. Reactivation of Car by an agonist normalizes all features associated with experimental SFSS. The beneficial effects of Car activation are relayed through Foxm1, an essential promoter of the hepatocyte cell cycle. Deficiency in the CAR-FOXM1 axis likewise is evident in human SFSS. Activation of human CAR mitigates SFSS in humanized CAR mice and improves the culture of human liver slices.

Conclusions

Impaired hepatic Car-Foxm1 signaling provides a first molecular characterization of liver that fails to recover after tissue loss. Our findings place deficient regeneration as a principal cause behind the SFSS and suggest CAR agonists may bear clinical potential against liver failure.

Lay summary

The unique regenerative capacity of liver has its natural limits. Following tissue loss that is too excessive, such as through extended resection in the clinic, liver failure may develop. This is known as small-for-size-syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; reactivation of Car through pharmacological means is sufficient to prevent or rescue the SFSS.