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, 62 (4), 1237-48

Histone Deacetylase 4 Promotes Cholestatic Liver Injury in the Absence of prohibitin-1

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Histone Deacetylase 4 Promotes Cholestatic Liver Injury in the Absence of prohibitin-1

Lucía Barbier-Torres et al. Hepatology.

Abstract

Prohibitin-1 (PHB1) is an evolutionarily conserved pleiotropic protein that participates in diverse processes depending on its subcellular localization and interactome. Recent data have indicated a diverse role for PHB1 in the pathogenesis of obesity, cancer, and inflammatory bowel disease, among others. Data presented here suggest that PHB1 is also linked to cholestatic liver disease. Expression of PHB1 is markedly reduced in patients with primary biliary cirrhosis and biliary atresia or with Alagille syndrome, two major pediatric cholestatic conditions. In the experimental model of bile duct ligation, silencing of PHB1 induced liver fibrosis, reduced animal survival, and induced bile duct proliferation. Importantly, the modulatory effect of PHB1 is not dependent on its known mitochondrial function. Also, PHB1 interacts with histone deacetylase 4 (HDAC4) in the presence of bile acids. Hence, PHB1 depletion leads to increased nuclear HDAC4 content and its associated epigenetic changes. Remarkably, HDAC4 silencing and the administration of the HDAC inhibitor parthenolide during obstructive cholestasis in vivo promote genomic reprogramming, leading to regression of the fibrotic phenotype in liver-specific Phb1 knockout mice.

Conclusion: PHB1 is an important mediator of cholestatic liver injury that regulates the activity of HDAC4, which controls specific epigenetic markers; these results identify potential novel strategies to treat liver injury and fibrosis, particularly as a consequence of chronic cholestasis.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Reduced PHB1 levels are associated with cholestatic liver disease
(A) PHB1 levels in normal healthy liver (NL) and PBC human samples. PHB1 mRNA levels in human (B) NL, biliary atresia (BA), Alagille syndrome (ALS) and parenteral nutrition-associated liver disease (TPN) and (C) NL and BCLC A and B stage viral and alcoholic liver cirrhosis. (D) PHB1 levels in human NL, viral and alcoholic cirrhosis. PHB1 (E) protein and (F) gene expression in WT mice at different time points after BDL. (Values are mean ± Stdev. *p<0.05, **p<0.01, ***p<0.001 [PBC, BA, ALS, Virus or Alcohol vs NL, BDL vs Control).
Figure 2
Figure 2. The absence of PHB1 predisposes to liver injury
(A) Kaplan Meier curve, (B) Caspase 3 activity, (C) WB analysis with the indicated antibodies, (D) H&E, CK19, αSMA, Sirius red and F4/80 staining in livers and (E) AST, ALT and bilirubin levels in serum from WT, shPHB1 and shOPA1 livers 14 days after BDL. (F) qPCR analysis of the indicated genes in the biliary trees (n=2) isolated from WT and Phb1 KO mice 7 days after BDL. (Values are mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 [shPHB1 and shOPA1 vs Control, Phb1 KO vs WT).
Figure 3
Figure 3. HDAC4 expression in Phb1 KO mice
HDAC4 expression in (A) liver sections from WT and Phb1 KO mice at basal conditions and after BDL (left) and WT and Phb1 KO livers and hepatocytes by WB (right), (B) WT and Phb1 KO livers at basal conditions and after BDL at mRNA level and (C) nuclear and cytosolic fractions from WT and Phb1 KO livers and hepatocytes. (D) IP of PHB1 and WB against HDAC4 in WT hepatocytes stimulated with DCA. (E) HDAC4 in human samples from NL and PBC. (Values are mean ± SEM. *p<0.05 [Phb1 KO vs WT; PBC vs NL).
Figure 4
Figure 4. Parthenolide reduces liver damage after BDL in Phb1 KO mice
(A) Kaplan Meier curve, (B) H&E, αSMA and TUNEL staining, (C) indicated genes expression, (D) TNFα levels measured by ELISA and (E) HDAC4 levels in control and parthenolide treated Phb1 KO animals after BDL. (F) Caspase 3 activity after DCA (100μM) (upper panel) and WB against HDAC4 (lower panel) in WT, Phb1 KO, Phb1 KO treated with parthenolide and Phb1 KO overexpressing HDAC4 treated with parthenolide primary hepatocytes. (Values are mean ± SEM. *p>0.05, **p>0.01 [Parthenolide vs Phb1 KO, Phb1 KO vs WT and Parthenolide + HDAC4 vs Parthenolide]).
Figure 5
Figure 5. Parthenolide delays liver fibrosis in Phb1 KO mice
(A) Indicated genes expression, (B) TNFα levels measured by ELISA and (C) HDAC4 levels in control and parthenolide treated Phb1 KO animals. Values are mean ± SEM. *p > 0.05, **p<0.01 [Parthenolide vs Phb1 KO]).
Figure 6
Figure 6. HDAC4 silencing protects Phb1 KO mice from bile acid injury
(A) HDAC4, H&E, Sirius red, CK19 and F4/80 staining, (B) WB with the indicated antiboides and (C) expression of the indicated genes on livers from Phb1 KO siControl and siHDAC4 animals 7 days after BDL. (Values are mean ± SEM. *p> 0.05, **p<0.01 [siHDAC4 vs siControl]).

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