710 Different free fatty acids (FFA) affect steatosis extent and hepatocyte apoptosis. Evidence from an in vitro study

710 Different free fatty acids (FFA) affect steatosis extent and hepatocyte apoptosis. Evidence from an in vitro study
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  08. Alcoholic liver disease, NAFLD and drug induced liver disease 261 in NASH suggesting a defect in CE secretion and increased cholesterol synthesis and/or uptake. There is a general depletion of PUFAs and increase in cholesterol/PL ratio in NASH which may contribute to cell injury. NASH is associated with LPs which may reflect oxidative stress and also contribute to cell injury and inflammation. ~A MULTICENTRIC PROSPECTIVE ASSESSEMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE IN FRENCH PATIENTS WITH CHRONIC UNEXPLAINED HYPERTRANSAMINASEMIA V. Ratziul, J.F. Cadranel 2, B. Le Bail 3, X. Causse 4, D. Capron 5, C. Renou 6, C. Pilette 7, V. Oules 8, E. Gelsi 9, F. Oberti 1~ N. Le Provost 11 , V. de Ledinghen 3. 1Paris, 2Creil, 3Bordeaux, 4 0rldans, 5Amiens, 6Hy~res, 7 Le Mans, 8Marseille, 9Nice, 1~ France Background and Aims Only retrospective series documenting non- alcoholic fatty liver disease (NAFLD) in patients (pts) with increased aminotransferase levels are available. This prospective multicentric French study aimed to assess the prevalence and characteristics of NAFLD among pts with chronically elevated aminotransferases. Patients and Methods 248 consecutive pts from 21 hospitals were eval- uated. Exclusion criteria were: alcohol consumption >40 g/day, HCV or HBV infection, drug-induced liver injury, autoimmune or genetic liver disease. Liver biopsy was performed in all pts and interpreted by a single pathologist. Results Sex ratio was 0.62 and mean age 46.6 years. Mean daily alcohol was 11 g while 55% of pts abstained from alcohol. 9% of pts had diabetes and 16% arterial hypertension (HTN). Mean BMI was 27.7 kg/m 2 (• Three main histologic categories were noted: NAFLD 58% (bland steatosis 26%, steatohepatitis 32%), normal/subnormal liver (18.5%), and miscellaneous (23.5%). Compared with pts with bland steatosis, those with steatohepatitis were older, had more severe insulin resistance (higher BMI, prevalence of HTN, fasting insulin, HOMA index, serum glucose, triglycerides, serum ferritin, lower HDL), more advanced steatosis, higher prevalence of bridging fibrosis/cirrhosis (57% vs 16%, p < 0.001). Com- pared with patients with normal/subnormal liver, those with bland steatosis had higher BMI and higher serum glucose, triglycerides and ferritin, higher HOMA scores (2.5 vs 2.1, p 0.067) and lower levels of HDL. Age, BMI, HOMA index and serum triglycerides were independently associated with steatohepatitis, with an odds ratio of 3.8, 95%CI 1.9 7.5, p <0.001) for age >50 years, 6.2 (2.8 13.5, p <0.001) for BMI>25 kg/m 2, and 3.4 (1.7 6.7, p<0.001) for a HOMA index >3. Bridging fibrosis/cirrhosis was present in 57% ofpts with steatohepatitis vs. 15% of those without (p < 0.001). Two-thirds ofpts with bridging fibrosis/cirrhosis had steatohepatitis (OR 7.2, 3.9 13.4, p < 0.001). Eight of the 9 cirrhotic pts had steatohepatitis. Conclusions Half of the pts with chronic, unexplained aminotransferase elevation had NAFLD. Pts with steatohepatitis had more profound insulin resistance and more severe fibrosis than those without. These results demonstrate the importance of recognizing NAFLD as a distinct and frequent entity with significant potential for liver fibrosis. DIFFERENT FREE FATTY ACIDS FFA) AFFECT STEATOSIS EXTENT AND HEPATOCYTE APOPTOSIS. EVIDENCE FROM AN IN VITRO STUDY M. Ricchi 1 M.R. Odoardi 1 L. Carulli 1 M.L. Bormioli 1 C. Anzivino 1 M. Bertolotti 1 A. Lonardo 2, N. Carulli 1 P. Loria 1 1Dipartimento Misto di Medicine e Specialit~ Mediehe, Policlinico di Modena, Modena, Italy, 2Unita Operativa di Medicina Interna e Gastroenterologia, Nuovo Ospedale Civile-Estense, Baggio Vara (MO), Italy Background: The prevalence of NAFLD varies in different countries and the role of composition of alimentary fat remains unexplored. Aim: Evaluate the effect of monoinsatured (oleic acid) and saturated (palmitic acid) FFA on the extent of lipid storage and cytotoxicity in different hepatocyte cell lines. Method In HepG2, WRL-68 and HUH-7 cell lines steatosis was in- duced by adding palmitic acid (0.33mM and 0.66mM), oleic acid (0.66 mM and 1.33 mM) and mixtures (palmitic/oleic ratio 1:2) of FFAs (palmitic 0.33 mM + oleic 0.66 mM or palmitic 0.66 mM + oleic 1.33 mM) to cell medium. After a 24 h incubation period, steatosis was demonstrated by red oil-O-staining and transmission electron microscopy (TEM). Extent of triglyceride (TG) storage was expressed as TG (mg/dl)/protein con- tent (mg/ml) in cells lysates. Apoptosis was evaluated by DAPI staining and caspases 3/7 activity. Results At red oil-O-staining and TEM, all type of cells were full of lipid droplets. For identical treatments, HepG2 displayed an amount of TG/mg protein greater than WRL68 but far less that that found in HUH7. For each set of experiments, the amount of TG/mg protein increased with increasing concentration of FFAs in the medium. In HepG2 cells, for or a given concentration, oleic acid induced a greater (p < 0.05) TG storage (80• mg) than palmitic (55• mg). The extent of apoptosis increased with increasing concentration of both FFAs. At com- parable concentrations, palmitic induced a significantly higher (p < 0.01) apoptosis detected by caspases 3/7 activity (34,907• RFLU/gg pro- tein) than oleic acid (3437• RFLU/gg protein), despite the fact that the lipid storage in oleic-treated cells was greater. Mixtures of oleic and palmitic acid at the highest concentrations induced an extent of apoptosis lower (p < 0.01) than that found with palmitic alone. DAPI staining showed the same trend. In WRL-68 and HUH-7 cells a similar trend was found. However expression of genes involved in apoptotic/metabolic pathways was different for each cell line. Conclusions Cellular models of steatosis morphologically mimic human steatosis. Cell line type, FFAs structure and concentrations are important determinants of the extent TG storage and apoptosis. Oleic, although more steatogenic, is less toxic than palmitic and, when associated to palmitic, decreases its toxicity. PENTOXIFYLLINE PROTECTS GENETICALLY OBESE MICE FROM ETHANOL-INDUCED HEPATIC APOPTOSIS M.A. Robin 1 C. Demeilliers 1 A. Sutton 1 V. Paradis 2, C. Maisonneuve 1 S. Dubois 2, O. Poirel 1 P. Lett~ron 1 D. Pessayre 1 B. Fromenty 1 I lNSERM U481, UFR Denis' Diderot Site Biehat, Paris', France, 2Service Central d'Anatomie et de Cytologic Pathologiques, Hdpital Beaujon, Clichy, France Background and Aims Both obesity and alcohol can cause oxidative stress, cytokine induction, and steatohepatitis. To determine the conse- quences of their combination, we compared the hepatic effects of moderate ethanol binges in lean and obese ob/ob mice. Methods Mice received water or ethanol (2.5 g/kg) by gastric intubation daily for 4 days, and were killed 2 hours after the last administration. Some obese mice also received pentoxifylline, an inhibitor of tumor necrosis factor-alpha (TNF-~) production, before each ethanol administration. Results Serum ethanol concentrations were similar in lean and obese mice (1.4• and 1.2• g/L, respectively). There was a 5-fold increase in plasma alanine aminotransferase (ALT) in ob/ob mice compared to lean mice, and ethanol intoxication further increased ALT in obese mice (p 0.06). Pentoxifylline tended to reduce ALT in naive ob/ob mice and significantly suppressed ALT in intoxicated obese mice. In lean mice, mod- erate ethanol doses did not increase plasma TNF-~ and hepatic caspase-3 activity, but triggered some apoptotic hepatocytes. Naive ob/ob mice had a few necrotic and apoptotic hepatocytes, but exhibited little oxidative stress, possibly because of adaptive increases in manganese superoxide dismutase, heat shock protein 70 (Hsp70) and mitochondrial cytochrome c. In contrast to lean mice, alcohol administration to ob/ob mice did not increase oxidative stress despite increased CYP2E1. However, it increased
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