POSTERS Our findings demonstrate a novel role of Hedgehog signaling in lipid metabolism which dominates with a more periportal distribution, whereas de...

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POSTERS Our findings demonstrate a novel role of Hedgehog signaling in lipid metabolism which dominates with a more periportal distribution, whereas depletion of APC leads to a pericentralization of hepatic functions, associated with reduced urea production and glutamine uptake. The increase in pyruvate uptake with simultaneously decreased citrate and alpha-ketoglutarate production implicates its use for fatty acid synthesis. Investigations on Hedgehog signaling have demonstrated a prominent role in lipid metabolism, which is also subject to liver zonation. 1278 URSODEOXYCHOLIC ACID COUNTERACTS LIPOTOXICITY AND INDUCES UNFOLDED PROTEIN RESPONSE IN MORBIDLY OBESE PATIENTS M. Mueller1,2 , H.-U. Marschall3 , T. Claudel1 , M. Wagner2 , P. Fickert2 , C. Lackner4 , C. Einarsson5 , A. Thorell6 , M. Trauner1 . 1 Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, 2 Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine, Medical University of Graz, Graz, Austria; 3 Institute of Medicine, Dept. of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 4 Institute of Pathology, Medical University of Graz, Graz, Austria; 5 Karolinska Institutet, Dept. of Medicine, Karolinska University Hospital Huddinge, Huddinge, 6 Karolinska Institutet, Dept. of Surgery, Ersta Hospital, Stockholm, Sweden E-mail: [email protected] Background and Aim: Expansion of white adipose tissue (WAT) with elevated fatty acid (FA) flux to the liver as a result of insulin resistance plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Treatment with taurine-conjugated UDCA (TUDCA) improved ER stress and steatosis in mice. Although UDCA is used in various liver diseases, its action on unfolded protein response (UPR) in humans remains to be elucidated. We aimed to investigate the impact of UDCA in morbidly obese patients on UPR and hepatic/WAT lipid metabolism as well as lipid partitioning along the WAT-liver-axis. Methods: 20 morbidly obese patients receiving UDCA (20 mg/kg/day) for 21 days prior to bariatric surgery were compared to 20 morbidly obese controls without UDCA. Serum liver enzymes, lipids and bile acids (BAs) were measured before and after treatment. Biopsies from liver and visceral WAT (vWAT) were obtained during surgery to determine expression of genes involved in lipid partitioning by qRT-PCR and investigate total and free FA profiles by gas chromatographic/negative ion chemical ionization mass spectrometry (GC-NICI/MS) and GC-electron impact/MS, respectively. Results: UDCA improved serum liver enzymes, increased triglycerides (TG) and decreased free FA serum concentrations (p ≤ 0.05). In vWAT, UDCA increased oleic acid (OA) in the total FA-pool and lowered free FA concentrations of lipotoxic palmitic and stearic acid by 84.8±19.2% and 94.0±18.4%, respectively. In line, SCD, the enzyme generating OA, was up-regulated in vWAT (p ≤ 0.01). In liver, changes in lipogenesis were reflected by equally up-regulated SCD but unchanged SREBP1c and FAS. UDCA expanded the BA pool (p ≤ 0.05) with an UDCA enrichment of 87.7±3.7%. Furthermore, hepatic genes involved in BA (CYP7A1, p ≤ 0.05) and cholesterol biosynthesis (SREBP2, p ≤ 0.01; HMGCR, p ≤ 0.05) were induced. This was substantiated by increased serum C4 (p ≤ 0.001) and desmosterol (p ≤ 0.05) levels. UDCA stimulated hepatic UPR gene expression (GRP78, CHOP; p ≤ 0.01). Notably, activation of CHOP, a known apoptosis inducer, did not up-regulate apoptosis reflected by stable BAK, BAX and BCL2 expression. Conclusions: UDCA improves hepatic injury, profoundly changes BA/cholesterol synthesis and protects liver from ER stress by inducing UPR. Furthermore, UDCA alters lipid partitioning in vWAT and liver counteracting lipotoxicity in morbid obesity.

1279 MULTIPLE ORGAN CROSSTALKS FOR HEPATIC STEATOSIS: ROLES OF MYOKINE (FGF2, MYOSTATIN, AND IRISIN) M. Nakamuta1 , M. Kohjima1 , T. Yoshimoto1 , M. Kurokawa1 , T. Nakamura1 , M. Iwata1 , N. Fukushima1 , K. Fukuizumi1 , N. Fujimori1 , K. Kawabe1 , K. Haraguchi1 , Y. Sumida1 , N. Harada1 , T. Ryu2 , Y. Wada2 , Y. Takami2 , H. Saitsu2 , T. Utsunomiya3 , M. Simada3 , H. Nomura4 , M. Enjoji5 . 1 Gastroenterology, Clinical Research Center, 2 Hepato-Biliary-Pancreatic Surgery, Clinical Research Center, Kyushu Medical Center, Fukuoka, 3 Digestive and Pediatric Surgery, Tokushima University, Tokushima, 4 Gastroenterology, Shin-Kokura Hospital, Kitakyushu, 5 Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan E-mail: [email protected] Background: The liver has a critical role in metabolism, as it is involved in the synthesis, storage, metabolism, and repartition of nutrition like fat as well as carbohydrate. Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver function tests, and it is characterized by lipid accumulation in hepatocytes. NAFLD is often accompanied with obesity, hyperlipidemia, diabetes, and/or, insulin resistance, which are simultaneously affect multiple organs. Multiple organ relationship such as between visceral fat, subcutaneous fat, muscle, and liver could be a key for lipid accumulation in the hepatocyte. Here we focused on myokines, hormones or cytokines secreted from muscle cells, and examined the organ crosstalk between muscles and other tissue. Methods: We collected visceral fat, subcutaneous fat, muscle, and liver tissue from surgery patients granted permission (n = 139) and extracted mRNA from the tissue. Expression of the genes was analyzed using quantitative PCR analysis. All experimental procedures were carried out under a protocol approved by ethical committee at Kyushu Medical Center. Results: Genes involved in lipid metabolism in each organ had positive relationship with the genes with different tissue. FGF2 expression in muscle was significantly correlated with FAS and SREBP1c expression in the liver (r = 0.4403, p < 0.0001, and r = 0.5095, p < 0.0001, respectively). Furthermore, the expression of CD36 and PPARg in the liver was strongly associated with muscle FGF2 expression (r = 0.2040, p = 0.0287, and r = 0.2659, p = 0.0046, respectively). The expression of myostatin and FNDC5 (a precursor protein of irisin) in rectus muscle had strong relationship with adipose mass volume, and negatively correlated with ACC1 expression in visceral fat, while no mutuality could be detected with the lipid metabolism-related genes in the liver. Conclusion: It has been recently reported that up-regulated muscle FGF2 expression by aging results in breaking the quiescence of muscle stem cells and taking away their self-renewing capacity, leading age-related sarcopenia. FGF2 might play a crucial role in hepatic steatosis as well as muscle maintenance, particularly in aged patients. 1280 CHOLESTEROL OVERLOAD ENHANCES LIVER DAMAGE AND IMPAIRS ORGAN REPAIR IN MICE SUBJECTED TO BILE DUCT LIGATION 1 1 N. Nuno-L ˜ ambarri ´ , S. Salas-Silva1 , M. Dom´ınguez-Perez ´ , D. Clavijo-Cornejo1 , M. Palestino-Dom´ınguez1 , C. Garc´ıa-Ruiz2 , 2 1 J.C. Fernandez-Checa ´ , L.E. Gomez-Quiroz ´ , M.C. Gutierrez ´ Ruiz1 . 1 Departamento de Ciencias de la Salud, UAM-Iztapalapa, D.F, Mexico; 2 Unidad de H´ıgado, Centro Esther Koplowitz, MDiM, Hospital Cl´ınic i Provincial y CIBEREHD, IDIBAPS, Barcelona, Spain E-mail: [email protected] Nonalcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome, defined by the deposition of fat in more than 5% of hepatocytes. It is well known that lipid overload, particularly cholesterol, sensitizes to hepatocellular damage. We were focused

Journal of Hepatology 2013 vol. 58 | S409–S566