- Email: [email protected]
[776] Withdrawn
OK. ALCOHOLIC LIVER DISEASE, NAFLD AND DRUGINDUCED LIVER DISEASE
17751 OVEREXPRESSION OF PIGMENT EPITHELIUM-DERIVED FACTOR PREVENTS FAT STORAGE, INFLAMMATION AND NEOPLASTIC FORMATION IN THE LIVER OF MICE STEATOHEPATITIS MODEL T. Yoshida, S. Yamagishi, H. Koga, K. Nakamura, T. Matsui, T. Imaizumi, T. Ueno, M. Sata. Depurtments off’lnternalMedicine, Kurume Uniuer~sih~ School of Medicine, Kuvunie, J u p n E-mail: [email protected] Backgound and Aims: Pigment epithelium-derived factor (PEDF) was first purified from retinal pigment epithelial cells as a factor with neuronal differentiating activity. We, along with others, have recently shown that PEDF is a potent inhibitor of angiogenesis and inflammation in various types of cells through its anti-oxidative property. Since oxidative stress generation is considered to be involved in the development and progression of non-alcoholic steatohepatitis (NASH), it is conceivable that PEDF may play a protective role against NASH. In this study, we examined whether and how overexpression of PEDF slowed the progression of NASH in mice model. Methods: Mice were fed methionine and choline deficient (MCD) diet with or without infection of adenovirus expressing PEDF (Ad-PEDF) for up to 16 weeks. Effects of PEDF overexpression on NASH were evaluated biochemically and histologically. Results: Administration of Ad-PEDF was found to significantly decreased serum levels of ALT and AST and hepatic fat storage in MCD-fed mice. Reactive oxygen species generation and infiltration of inflammatory cells in the liver and hepatic fibrosis were also prevented by the treatment of Ad-PEDE Quantitative real time RT-PCR revealed that TNF-alpha, 1L-6, IL-lfl, TGF-beta, collagen-1, collage-3, PPAR-gamma and SREBP-1 genes were up-regulated in MCD-fed mice, all of which were suppressed by the overexpression of Ad-PEDF. In addition, administration of Ad-PEDF significantly decreased GST-P positive areas which reflect neoplastic formation of the liver in MCD-fed mice. Conclusions: These results demonstrated for the first time that PEDF could slow the development and progression ofNASH in MCD-fed mice through its anti-oxidative and anti-inflammatory properties. Our present study suggests that PEDF may be a novel therapeutic strategy for the treatment of NASH.
17761 Withdrawn 17771 LONG TERM NUTRITIONAL INTAKE AND THE RISK FOR NON-ALCOHOLIC FATTY LIVER DISEASE A POPULATION BASED STUDY S. Zelber-Sa~i’,~, D. Nitzan-Kaluski’,2, Z. Halp er n ’ ~~, R. O r e r ~ ’ , ~ ’The . Lioev Unit, Depurtnient of‘ Gustroenterology, Tel-Auiu Souvusky Medical Center, Tel-Auiu; ’The Food and Nutrition Administrution, Ministry of Health; The Suckler Fuculw of Medicine, Tel-Aoio Unioersiw, Tel-Aoio, Israel E-mail: [email protected] Background and Aims: Weight loss is considered therapeutic for patients with non-alcoholic fatty liver disease (NAFLD). However, there is no epidemiological evidence that dietary habits are associated with NAFLD. It remains uncertain whether diets that are enriched with certain types of food are more likely to cause fatty liver than other types of diets Aims: to identify specific dietary patterns that may be associated with NAFLD in order to establish the nutritional recommendations. Methods: A cross-sectional study of a sub-sample (n=375) of the first Israeli national health and nutrition survey. Exclusion criteria were any known aetiology for secondary NAFLD. Participants underwent an abdominal ultrasound, biochemical tests, and dietary and anthropometric evaluations. A detailed semiquantitative food frequency questionnaire (FFQ)
S291
was administered to participants. The FFQ was assembled by the Food and Nutrition Administration, Ministry of Health and is composed of I 1 I food items with specified serving sizes. For each food item, participants indicated their average frequency of consumption over the past year. Results: Three hundred forty nine randomized volunteers [52.7‘%,male, mean age 50.7f10.4 SD (24-75)] were included in the analysis. The mean BMI was 27.2&4.5. The prevalence of primary NAFLD, diagnosed by ultrasound, was 30.9% ( n = 108) (95%CI 260/;1-36?4). Controlling for age, gender and total calories, intake of carbohydrates from soft drinks and protein from all kinds of meat or fish were significantly associated with increased risk for NAFLD [OR = I .23, 1.04-1.46 95% CT per 2 1.2 giday increment ( I standard deviation) and OR = I .29, 1.08-1.9 I 95% CT per 25.3 giday increment ( I standard deviation) respectively]. Intake of protein from fish rich in omega-3 reduced the risk for NAFLD [OR=0.81, 0.68-0.97 95% C1 per 3.3 &/dayincrement (1 standard deviation)]. Conclusions: Higher intake of soft drinks and all kinds of meat or fish is significantly associated with an increased risk ofNAFLD, or may represent an unhealthy dietary pattern that might be associated with NAFLD. On the other hand, intake of fish rich in omega-3 appears to reduce the risk for NAFLD.
17781 AMELIORATION OF NON ALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND THE METABOLIC SYNDROME IN DIABETIC COHEN RATS IS ASSOCIATED WITH REDUCED PANCREATIC INJURY E. Zirmond’, S.W. Zangen2, 0. Pappo3, L. Zolotarov’, 1. Raz2, Y. Tlan’, M. Margalit’ . ‘Liuer Unit, Department of Medicine; ’Diuhetes Unit, Depurtment of Medicine; ‘Puthology Depurtment, Hudussah-Hebrew Uniuer~sityMedical Center, Jerusulem, I,srael E-mail: [email protected] The Cohen rat is a non-insulin resistant model of type 2 diabetes that features hepatic steatosis and elevated serum transaminases. [3-glucosylceramide (GC) and (3-lactosylceramide (LC) are naturallyoccurring glycolipids that were shown to exert beneficial metabolic and immune-modulatory effects in several experimental models of NAFLD. Objectives: To determine the effect of GC, LC and a 1 : 1 combination of GC and LC (TGL) on hepatic steatosis and the metabolic syndrome in diabetic Cohen rats. Methods: Four groups of rats were studied. Animals were treated by daily intraperitoneal injections of GC (A), LC (B), IGL (C), or PBS (D) for 45 days. Assessment of NAFLD was performed by MR imaging, examination of liver histology and measurement of serum transaminases. Metabolic follow-up parameters included body weight, oral glucose tolerance test (OGTT), serum lipids and pancreatic histology. Immune modulation was assessed by FACS analysis of lymphocytes subsets. Results: Administration of LC and TGL resulted i n reduced hepatic fat content (MRT ST index 0.23, 0.15, 0.14 and 0. I9 in groups A, B C and D, respectively, P i 0.05) and serum transaminases (mean serum ALT 268, 251, 174 and 301 IUIL; mean serum AST 75, 59, 45 and 83 IUIL, in groups A, B C and D, respectively, P i 0.05). In the OGTT, glycolipids significantly reduced the area under the glucose curve (25642, 25413, 23757 and 30333 mg/dl/l20’, respectively, p < 0.05) and increased the area under the insulin curve (100, 79, 131 and 74pg/1/120’, respectively, P < 0.05). Treatment with IGL resulted in significantly reduced serum triglycerides ( I .8 vs. 2.4 mmolil in groups C and D, respectively, p 0.05). In contrast to the marked fat infiltration, atrophy and fibrosis characteristic of control group pancreata (group D), pancreatic histology was markedly improved in all treated groups. Increased intrahepatic CD8 T lymphocyte trapping in LC and TGL-treated animals was observed. Conclusions: The combination of GC and LC had a therapeutic benefit exceeding that of either glycolipid alone, and was associated with marked amelioration of pancreatic injury and improved insulin secretion in treated animals. Administration of P-glycolipid combinations holds promise as a therapeutic modality for NAFLD and the metabolic syndrome.
17751 OVEREXPRESSION OF PIGMENT EPITHELIUM-DERIVED FACTOR PREVENTS FAT STORAGE, INFLAMMATION AND NEOPLASTIC FORMATION IN THE LIVER OF MICE STEATOHEPATITIS MODEL T. Yoshida, S. Yamagishi, H. Koga, K. Nakamura, T. Matsui, T. Imaizumi, T. Ueno, M. Sata. Depurtments off’lnternalMedicine, Kurume Uniuer~sih~ School of Medicine, Kuvunie, J u p n E-mail: [email protected] Backgound and Aims: Pigment epithelium-derived factor (PEDF) was first purified from retinal pigment epithelial cells as a factor with neuronal differentiating activity. We, along with others, have recently shown that PEDF is a potent inhibitor of angiogenesis and inflammation in various types of cells through its anti-oxidative property. Since oxidative stress generation is considered to be involved in the development and progression of non-alcoholic steatohepatitis (NASH), it is conceivable that PEDF may play a protective role against NASH. In this study, we examined whether and how overexpression of PEDF slowed the progression of NASH in mice model. Methods: Mice were fed methionine and choline deficient (MCD) diet with or without infection of adenovirus expressing PEDF (Ad-PEDF) for up to 16 weeks. Effects of PEDF overexpression on NASH were evaluated biochemically and histologically. Results: Administration of Ad-PEDF was found to significantly decreased serum levels of ALT and AST and hepatic fat storage in MCD-fed mice. Reactive oxygen species generation and infiltration of inflammatory cells in the liver and hepatic fibrosis were also prevented by the treatment of Ad-PEDE Quantitative real time RT-PCR revealed that TNF-alpha, 1L-6, IL-lfl, TGF-beta, collagen-1, collage-3, PPAR-gamma and SREBP-1 genes were up-regulated in MCD-fed mice, all of which were suppressed by the overexpression of Ad-PEDF. In addition, administration of Ad-PEDF significantly decreased GST-P positive areas which reflect neoplastic formation of the liver in MCD-fed mice. Conclusions: These results demonstrated for the first time that PEDF could slow the development and progression ofNASH in MCD-fed mice through its anti-oxidative and anti-inflammatory properties. Our present study suggests that PEDF may be a novel therapeutic strategy for the treatment of NASH.
17761 Withdrawn 17771 LONG TERM NUTRITIONAL INTAKE AND THE RISK FOR NON-ALCOHOLIC FATTY LIVER DISEASE A POPULATION BASED STUDY S. Zelber-Sa~i’,~, D. Nitzan-Kaluski’,2, Z. Halp er n ’ ~~, R. O r e r ~ ’ , ~ ’The . Lioev Unit, Depurtnient of‘ Gustroenterology, Tel-Auiu Souvusky Medical Center, Tel-Auiu; ’The Food and Nutrition Administrution, Ministry of Health; The Suckler Fuculw of Medicine, Tel-Aoio Unioersiw, Tel-Aoio, Israel E-mail: [email protected] Background and Aims: Weight loss is considered therapeutic for patients with non-alcoholic fatty liver disease (NAFLD). However, there is no epidemiological evidence that dietary habits are associated with NAFLD. It remains uncertain whether diets that are enriched with certain types of food are more likely to cause fatty liver than other types of diets Aims: to identify specific dietary patterns that may be associated with NAFLD in order to establish the nutritional recommendations. Methods: A cross-sectional study of a sub-sample (n=375) of the first Israeli national health and nutrition survey. Exclusion criteria were any known aetiology for secondary NAFLD. Participants underwent an abdominal ultrasound, biochemical tests, and dietary and anthropometric evaluations. A detailed semiquantitative food frequency questionnaire (FFQ)
S291
was administered to participants. The FFQ was assembled by the Food and Nutrition Administration, Ministry of Health and is composed of I 1 I food items with specified serving sizes. For each food item, participants indicated their average frequency of consumption over the past year. Results: Three hundred forty nine randomized volunteers [52.7‘%,male, mean age 50.7f10.4 SD (24-75)] were included in the analysis. The mean BMI was 27.2&4.5. The prevalence of primary NAFLD, diagnosed by ultrasound, was 30.9% ( n = 108) (95%CI 260/;1-36?4). Controlling for age, gender and total calories, intake of carbohydrates from soft drinks and protein from all kinds of meat or fish were significantly associated with increased risk for NAFLD [OR = I .23, 1.04-1.46 95% CT per 2 1.2 giday increment ( I standard deviation) and OR = I .29, 1.08-1.9 I 95% CT per 25.3 giday increment ( I standard deviation) respectively]. Intake of protein from fish rich in omega-3 reduced the risk for NAFLD [OR=0.81, 0.68-0.97 95% C1 per 3.3 &/dayincrement (1 standard deviation)]. Conclusions: Higher intake of soft drinks and all kinds of meat or fish is significantly associated with an increased risk ofNAFLD, or may represent an unhealthy dietary pattern that might be associated with NAFLD. On the other hand, intake of fish rich in omega-3 appears to reduce the risk for NAFLD.
17781 AMELIORATION OF NON ALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND THE METABOLIC SYNDROME IN DIABETIC COHEN RATS IS ASSOCIATED WITH REDUCED PANCREATIC INJURY E. Zirmond’, S.W. Zangen2, 0. Pappo3, L. Zolotarov’, 1. Raz2, Y. Tlan’, M. Margalit’ . ‘Liuer Unit, Department of Medicine; ’Diuhetes Unit, Depurtment of Medicine; ‘Puthology Depurtment, Hudussah-Hebrew Uniuer~sityMedical Center, Jerusulem, I,srael E-mail: [email protected] The Cohen rat is a non-insulin resistant model of type 2 diabetes that features hepatic steatosis and elevated serum transaminases. [3-glucosylceramide (GC) and (3-lactosylceramide (LC) are naturallyoccurring glycolipids that were shown to exert beneficial metabolic and immune-modulatory effects in several experimental models of NAFLD. Objectives: To determine the effect of GC, LC and a 1 : 1 combination of GC and LC (TGL) on hepatic steatosis and the metabolic syndrome in diabetic Cohen rats. Methods: Four groups of rats were studied. Animals were treated by daily intraperitoneal injections of GC (A), LC (B), IGL (C), or PBS (D) for 45 days. Assessment of NAFLD was performed by MR imaging, examination of liver histology and measurement of serum transaminases. Metabolic follow-up parameters included body weight, oral glucose tolerance test (OGTT), serum lipids and pancreatic histology. Immune modulation was assessed by FACS analysis of lymphocytes subsets. Results: Administration of LC and TGL resulted i n reduced hepatic fat content (MRT ST index 0.23, 0.15, 0.14 and 0. I9 in groups A, B C and D, respectively, P i 0.05) and serum transaminases (mean serum ALT 268, 251, 174 and 301 IUIL; mean serum AST 75, 59, 45 and 83 IUIL, in groups A, B C and D, respectively, P i 0.05). In the OGTT, glycolipids significantly reduced the area under the glucose curve (25642, 25413, 23757 and 30333 mg/dl/l20’, respectively, p < 0.05) and increased the area under the insulin curve (100, 79, 131 and 74pg/1/120’, respectively, P < 0.05). Treatment with IGL resulted in significantly reduced serum triglycerides ( I .8 vs. 2.4 mmolil in groups C and D, respectively, p 0.05). In contrast to the marked fat infiltration, atrophy and fibrosis characteristic of control group pancreata (group D), pancreatic histology was markedly improved in all treated groups. Increased intrahepatic CD8 T lymphocyte trapping in LC and TGL-treated animals was observed. Conclusions: The combination of GC and LC had a therapeutic benefit exceeding that of either glycolipid alone, and was associated with marked amelioration of pancreatic injury and improved insulin secretion in treated animals. Administration of P-glycolipid combinations holds promise as a therapeutic modality for NAFLD and the metabolic syndrome.