Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis.
BACKGROUND
Hepatocyte-specific NEMO/NF-κB deleted mice (NEMO(Δhepa)) develop spontaneous non-alcoholic steatohepatitis (NASH). Free fatty acids and bile acids promote DR5 expression. TRAIL/NK cell-mediated activation of TRAIL-R2/DR5 plays an important role during acute injury in NEMO(Δhepa) mice.


OBJECTIVE
To inhibit the progression of NASH in the absence of hepatocyte-NEMO/NF-kB signaling.


METHODS
NEMOf/f and NEMO(Δhepa) mice were fed with a low-fat diet, and with two anticholestatic diets; UDCA and NorUDCA. The impact of these treatments on the progression of NASH was evaluated.


RESULTS
We show that high expression of DR5 in livers from NEMO(Δhepa) mice is accompanied by an abundant presence of bile acids (BAs), misregulation of BA transporters and significant alteration of lipid metabolism-related genes. Additionally, mice lacking NEMO in hepatocytes spontaneously showed ductular response at young age. Unexpectedly, feeding of NEMO(Δhepa) mice with low-fat diet failed to improve chronic liver injury. Conversely, anti-cholestatic treatment with nor-ursodeoxycholic acid (NorUDCA), but not with ursodeoxycholic acid (UDCA), led to a significant attenuation of liver damage in NEMO(Δhepa) mice. The strong therapeutic effect of NorUDCA relied on a significant downregulation of LXR-dependent lipogenesis and the normalisation of BA metabolism through mechanisms involving cross-talk between Cyp7a1 and SHP. This was associated with the significant improvement of liver histology, NEMO(Δhepa)/NorUDCA-treated mice showed lower apoptosis and reduced CyclinD1 expression, indicating attenuation of the compensatory proliferative response to hepatocellular damage. Finally, fibrosis and ductular reaction markers were significantly reduced in NorUDCA-treated NEMO(Δhepa) mice.


CONCLUSIONS
Overall, our work demonstrates the contribution of bile acids metabolism to the progression of NASH in the absence of hepatocyte-NF-kB through mechanisms involving DR5-apoptosis, inflammation and fibrosis. Our work suggests a potential therapeutic effect of NorUDCA in attenuating the progression of NASH.
Department of Internal Medicine, University Hospital Aachen (RWTH), Aachen, Germany. ctrautwein@ukaachen.de
Naiara
N
Beraza
Lisa
L
Ofner-Ziegenfuss
Haksier
H
Ehedego
Mark
M
Boekschoten
Stephan C
SC
Bischoff
Michael
M
Mueller
Michael
M
Trauner
Christian
C
Trautwein
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018752:Diet, Fat-Restricted; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005234:Fatty Liver / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008055:Lipids / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; C514981:NEMO protein, mouse; D014580:Ursodeoxycholic Acid; C081331:24-norursodeoxycholic acid