studies

282A AASLD ABSTRACTS HEPATOLOGY, October, 2015
pioglitazone on mitochondrial respiration. In the db/db mouse
model of T2DM, DRX-065 significantly decreases blood glucose,
serum triglycerides, and fatty acids, as well as markers of
inflammation (cytokines, serum amyloid A). At a therapeutically
effective dose in mice, DRX-065 also does not induce weight
gain, unlike pioglitazone or d-S-pio. The effects of d-S-pio on
weight gain are expected based on its strong PPARg agonist
activity. Conclusion: We demonstrated in preclinical experiments
that the stabilized deuterated R-enantiomer of pioglitazone,
DRX-065, has pharmacological properties desirable
for the treatment of NASH (mitochondrial function modulation,
non-steroidal anti-inflammatory effects, and glucose lowering
effects) without the undesired PPARg-related weight gain side
effects. DRX-065 represents a potentially significant therapeutic
improvement over pioglitazone, a drug already recommended
off-label for the treatment of NASH.
Disclosures:
The following authors have nothing to disclose: Sheila H. DeWitt, Vincent
Jacques, Lex H. Van der Ploeg
144
Peretinoin, an acyclic retinoid, suppresses steatohepatitis
and development of tumorigenesis by activated
Atg16L1-dependent autophagy in mice fed an atherogenic
high-fat diet.
Hikari Okada 1 , Masao Honda 1 , Kai Takegoshi 1 , Taro Yamashita 1 ,
Naoto Nagata 2 , Toshinari Takamura 2 , Takuji Tanaka 3 , Shuichi
Kaneko 1 ; 1 Gastroenterology, Kanazawa University Graduate
School of Medical Science, Kanazawa, Japan; 2 Department of
Disease Control and Homeostasis, Kanazawa University Graduate
School of Medical Sciences, Kanazawa, Japan; 3 Cancer Research
and Prevention, The Tohkai Cytopathology Institute, Gifu, Japan
Objective Peretinoin, acyclic retinoid, is under phase III clinical
trials in Japan to prevent the recurrence and development of
HCC after surgical removal of the primary tumors. The mechanism
of peretinoin for preventing HCC remains unclear. Mice
fed an atherogenic high-fat diet (Ath HFD) developed steatohepatitis
followed by hepatic fibrosis and HCC progression
(Hepatology 2007). Here we investigated the suppressive
effects of peretinoin on steatohepatitis and tumorigenesis in
Ath HFD mice. Materials and Methods Three groups of 8-weekold
mice (n=15-20/group) were fed a control diet or Ath HFD
containing 0.01% or 0.03% peretinoin for 12, 30, and 60
weeks. Then, 0.01% peretinoin was added to the Ath HFD
at 40 weeks to examine the reversible effect of peretinoin on
established fibrosis and steatosis in the liver. The degree of liver
steatosis, hepatic fibrosis, tumor incidence, and liver weight
was calculated. Expression of IL6, IL1β TNFα, CEBPα, collagen
I/IV, pSTAT3, pNFkβ, ATG5, ATG7, ATG16L1, LC3b,
and Lamp2 was evaluated by immunohistochemical staining,
real-time PCR, and western blotting. The promoter analysis of
ATG16L1 was performed by reporter gene assay and ChIP
assay. Primary hepatocytes were isolated from male C57BL/6
mice treated Ath HFD for 12 weeks and the effect of peretinoin
on primary hepatocytes was evaluated in vitro. Results Mice
fed an Ath HFD developed liver steatosis and liver fibrosis after
12 and 30 weeks, and developed liver tumors after 60 weeks
at 70% frequency. Peretinoin markedly reduced steatosis and
fibrosis at 12 and 30 weeks and reduced tumor incidence to
approximately 30%. Expression of IL6, IL1β, TNFα, collagen
I/IV, pSTAT3, and pNFkβ was suppressed to approximately
60% in mice fed an Ath HFD containing peretinoin compared
with mice fed only an Ath HFD. We found peretinoin induced
autophagy that was shown by the increased autophagosome
formation by electron microscopy. We found increased LC3-II
and co-localization of autophagosome (LC3-II) and lysosome
(Lamp2) by immune fluorescent staining. Among various autophagy
related factors, peretinoin increased the expression of
Atg16L1 and promoted Atg16L1-dependent autophagy. In primary
hepatocyte, palmitic acid and IL6 suppressed the expression
of Atg16L1, while peretinoin rescued the Atg16L1 and
suppressed pSTAT3 and pNFkβ. We found peretinoin induced
the expression of CEBPα and CEBPα activated the promoter
activity of Atg16L1. Conclusion Peretinoin suppresses the development
of liver steatosis, inflammation, and tumorigenesis by
activating Atg16L1-dependent autophagy. These results support
the clinical efficacy of peretinoin for preventing HCC.
Disclosures:
Hikari Okada - Employment: Kanazawa University
Shuichi Kaneko - Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co.,
Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc,
Ajinomoto Co., Inc, Bristol Myers Squibb., Inc, Pfizer., Co., Inc, Astellas., Inc,
Takeda., Co., Inc, Otsuka„ÄÄPharmaceutical, Co., Inc, Eizai Co., Inc, Bayer
Japan, Eli lilly Japan
The following authors have nothing to disclose: Masao Honda, Kai Takegoshi,
Taro Yamashita, Naoto Nagata, Toshinari Takamura, Takuji Tanaka
145
Effects of norfloxacin therapy on survival in patients
with Child-Pugh class C cirrhosis: Results of a randomized,
double-blind, placebo-controlled, multicenter trial
Richard Moreau 1,2 , Laure Elkrief 2 , Christophe Bureau 3 , Jean-
Marc Perarnau 4 , Thierry Thevenot 5 , Faouzi Saliba 6 , Isabelle Ollivier-Hourmand
15 , Alexandre Louvet 7 , Pierre Nahon 8 , Frédéric
Oberti 9 , Rodolphe Anty 10 , Sophie Hillaire 11 , Blandine Pasquet 12 ,
Violaine Ozenne 13 , Marika Rudler 14 , Marie Angele Robic 3 , Louis
d’Alteroche 4 , Vincent Di Martino 5 , Pierre-Emmanuel Rautou 2 , Nathalie
Gault 16 , Didier Lebrec 1,2 ; 1 UMR S1149, Center for Research
on Inflammation (CRI), Inserm and Paris Diderot University, Clichy,
France; 2 DHU UNITY, Service d’hépatologie, Hôpital Beaujon,
APHP, Clichy, France; 3 Service d’hépato-gastroentérologie,, Hôpital
Purpan CHU Toulouse et Université Paul Sabatier, Toulouse,
France; 4 Unité d’Hépatologie, Hépatogastroentérologie, CHRU
Tours, Tours, France; 5 Service d’Hépatologie et de Soins Intensifs
Digestifs, Hôpital Jean Minjoz, Besançon, France; 6 Centre
Hépato-Biliaire, Hôpital Paul Brousse, APHP, Villejuif, France;
7 Service des maladies de l’appareil digestif, Hôpital Huriez, Lille,
France; 8 Service d’Hépatologie, Hôpital Jean Verdier, APHP,
Bondy, France; 9 Service d’hépato-gastroentérologie, CHU d’Angers,
Angers, France; 10 Pôle Digestif and Inserm 1065, CHU
de Nice, Nice, France; 11 Service de Médecine Interne, Hôpital
Foch, Suresnes, France; 12 Unité de recherche clinique Paris Nord,
Hôpital Bichat, APHP, Paris, France; 13 Hépato-gastroentérologie,
Hôpital Lariboisière, APHP, Paris, France; 14 Hépatologie, GH
Pitié-Salpêtrière, APHP, Paris, France; 15 Service d’hépato-gastro-entérologie
et nutrition and Unité 1930, CHU Côte de Nacre,
Caen, France; 16 Unité de recherche clinique Paris Nord, Hôpital
Beaujon, APHP, Clichy, France
Background & Aims: Whether long-term oral antibiotic therapy
using a fluoroquinolone should be used to improve prognosis in
patients with advanced cirrhosis is debated. Thus we addressed
this question by investigating the effects of the administration
of norfloxacin (a fluoroquinolone) in patients with advanced
cirrhosis. Methods: We performed a multicenter, double-blind
trial in which we randomly assigned patients with Child-Pugh
class C cirrhosis to once-daily 400 mg oral norfloxacin (144
patients) or placebo (147 patients) for 6 months. Surviving
patients were followed-up for further 6 months after treatment
cessation. The primary end point was overall survival at 6
months; secondary end points included overall survival at 3
and 12 months, and liver-related complications (bacterial infec-