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Effect of age and gender in the progression of NAFLD towards NASH in a juvenile mice model
Abstracts / Digestive and Liver Disease 47S (2015) e226–e235
Results: H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group (p < 0.0001). In contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT (r = 0.35; p < 0.0001) and the apoB/apoAI ratio (r = 0.43; p < 0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independently to MS components. Conclusions: In our study population, NAFLD was positively associated with carotid IMT. This association is independent of MS components but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio. http://dx.doi.org/10.1016/j.dld.2015.07.026 P3 EFFECT OF AGE AND GENDER IN THE PROGRESSION OF NAFLD TOWARDS NASH IN A JUVENILE MICE MODEL V. Marin 1,∗ , N. Rosso 1 , M. Dal Ben 1 , A. Raseni 2 , C. Degrassi 3 , C. Tiribelli 1,4 , S. Gazzin 1 1
Centro Studi Fegato- Liver Research Center, Fondazione Italiana Fegato, Italian Liver Foundation, Italy 2 S.C. Laboratorio Analisi Cliniche, IRCCS Burlo Garofalo, Italy 3 Medical Research Institute, Area Science Park Basovizza, Bldg Q2, Italy 4 Department of Medical Sciences, University of Trieste, Trieste, Italy Background: The increasing prevalence of pediatric NAFLD is considered a booming problem with worrying future outcome. Consistent pediatric models to mimic the clinical condition, as well as studies considering eventual gender differences, are still lacking. Aim: Develop and characterize a Juvenile NAFLD model. Males and females C57BL/6 mice, immediately after weaning was randomly assigned to control (CTRL) or high-fat high-carbohydrate diet (HFHCD). Materials and Methods: Animals had ad-libitum food for 16wks access. Body-weight, glycaemia, insulinemia, insulin resistance (IR), triglycerides, total cholesterol, HDL-C, LDL-C, ALT and liver histology were screened every 4wks and compared to CTRL. Results: Soon after the 1st week, HFHCD induced a significant bodyweight gain in both genders. Males, after 4weeks presented also hyperplasia of epididymal fat-pads and after week 12th, a significant hepatomegaly. Males showed earlier alteration of glycemia, insulinemia, IR, lipid profile and ALT. Interestingly, comparable body/blood alterations (with the exception of IR) were observed in females only at the 16thweek. Liver histology showed in both genders a mixed macro-microvesicular steatosis increasing steadily after the 8thweek. Inflammatory cells foci were observed in males from the beginning and increased over the time, whereas were absent in females. Surprisingly, both genders developed progressive fibrosis starting from the 8th week and rising steadily over the time. Conclusions: Our data show that the onset and progression of NAFLD at young age is faster than in adults. Moreover, in contrast with the common wisdom, we showed that liver injury in female is present even in absence of inflammation signs and IR.
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Funding: The present work was supported by MIUR (Art.13 D.LGS 297/99-Progetto Nutrizione e Salute) and by FIF in house grant. http://dx.doi.org/10.1016/j.dld.2015.07.027 P4 THERAPEUTIC APPROACH TO NAFLD/NASH: IS SILIMARIN ABLE TO AMELIORATE LIVER INJURY? V. Marin 1,∗ , S.E. Gambaro 1,5 , M. Dal Ben 1 , A. Raseni 2 , C. Degrassi 3 , C. Tiribelli 1,4 , S. Gazzin 1 , N. Rosso 1 1
Centro Studi Fegato, Liver Research Center, Fondazione Italiana Fegato, Italian Liver Foundation, Italy 2 S.C. Laboratorio Analisi Cliniche, IRCCS Burlo Garofalo, Italy 3 Medical Research Institute, Area Science Park Basovizza, Bldg Q2, Italy 4 Department of Medical Sciences, University of Trieste, Trieste, Italy 5 Università degli Studi di Trieste, Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Italy Background and aims: NAFLD is a chronic liver disease without a specific therapy available. The aim of this work is to study the nutraceutical properties of Silimarin added to high fat diet in a NASH juvenile mice model. Materials and methods: Obese females and males 11 weeksold C57BL/6 mice, fed with High Fat High Carbohydrates Diet (HFHCD) during their whole life1, were exposed to Silimarin (1 mg/animal/day) added to HFHCD for further 12 weeks. Animals exposed only to HFHCD were used as control. Silimarin effects in vivo were assessed in terms of bodyweight, BMI, HOMA-IR, lipidemia, hepatomegaly, hypertrophy of visceral adipose tissue and liver histology. Moreover, the expression of profibrogenic genes was assess in the liver. Results: The addition of Silimarin to the HFHCD during the treatment period decreased the liver weight and the visceral fat (p < 0.001); it decreased also glycaemia (p < 0.05) but did not improve the HOMA-IR since insulin levels were unchanged. Plasmatic LDL-C, TG, ALT, AST were significantly reduced (p < 0.05). Histology of the liver showed a slight, but not significant, reduction in inflammatory foci and fibrosis. From a molecular point of view, Silmarin significantly decreased (p < 0.05) the expression of ␣-SMA (hepatic stellate activation marker) and Collagen 1A1 suggesting a potential effect in improving the fibrogenesis. Conclusions: Silimarin added to the HFHC diet might exert beneficial effects mainly improving lipidemia, liver damage and decreasing fibrogenesis. This data is particularly relevant to overcome patient compliance to change dietary habits. Funding: The present work was supported by MIUR (Art.13 D.LGS 297/99-Progetto Nutrizione e Salute) and by FIF in house grant. http://dx.doi.org/10.1016/j.dld.2015.07.028
Results: H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group (p < 0.0001). In contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT (r = 0.35; p < 0.0001) and the apoB/apoAI ratio (r = 0.43; p < 0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independently to MS components. Conclusions: In our study population, NAFLD was positively associated with carotid IMT. This association is independent of MS components but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio. http://dx.doi.org/10.1016/j.dld.2015.07.026 P3 EFFECT OF AGE AND GENDER IN THE PROGRESSION OF NAFLD TOWARDS NASH IN A JUVENILE MICE MODEL V. Marin 1,∗ , N. Rosso 1 , M. Dal Ben 1 , A. Raseni 2 , C. Degrassi 3 , C. Tiribelli 1,4 , S. Gazzin 1 1
Centro Studi Fegato- Liver Research Center, Fondazione Italiana Fegato, Italian Liver Foundation, Italy 2 S.C. Laboratorio Analisi Cliniche, IRCCS Burlo Garofalo, Italy 3 Medical Research Institute, Area Science Park Basovizza, Bldg Q2, Italy 4 Department of Medical Sciences, University of Trieste, Trieste, Italy Background: The increasing prevalence of pediatric NAFLD is considered a booming problem with worrying future outcome. Consistent pediatric models to mimic the clinical condition, as well as studies considering eventual gender differences, are still lacking. Aim: Develop and characterize a Juvenile NAFLD model. Males and females C57BL/6 mice, immediately after weaning was randomly assigned to control (CTRL) or high-fat high-carbohydrate diet (HFHCD). Materials and Methods: Animals had ad-libitum food for 16wks access. Body-weight, glycaemia, insulinemia, insulin resistance (IR), triglycerides, total cholesterol, HDL-C, LDL-C, ALT and liver histology were screened every 4wks and compared to CTRL. Results: Soon after the 1st week, HFHCD induced a significant bodyweight gain in both genders. Males, after 4weeks presented also hyperplasia of epididymal fat-pads and after week 12th, a significant hepatomegaly. Males showed earlier alteration of glycemia, insulinemia, IR, lipid profile and ALT. Interestingly, comparable body/blood alterations (with the exception of IR) were observed in females only at the 16thweek. Liver histology showed in both genders a mixed macro-microvesicular steatosis increasing steadily after the 8thweek. Inflammatory cells foci were observed in males from the beginning and increased over the time, whereas were absent in females. Surprisingly, both genders developed progressive fibrosis starting from the 8th week and rising steadily over the time. Conclusions: Our data show that the onset and progression of NAFLD at young age is faster than in adults. Moreover, in contrast with the common wisdom, we showed that liver injury in female is present even in absence of inflammation signs and IR.
e227
Funding: The present work was supported by MIUR (Art.13 D.LGS 297/99-Progetto Nutrizione e Salute) and by FIF in house grant. http://dx.doi.org/10.1016/j.dld.2015.07.027 P4 THERAPEUTIC APPROACH TO NAFLD/NASH: IS SILIMARIN ABLE TO AMELIORATE LIVER INJURY? V. Marin 1,∗ , S.E. Gambaro 1,5 , M. Dal Ben 1 , A. Raseni 2 , C. Degrassi 3 , C. Tiribelli 1,4 , S. Gazzin 1 , N. Rosso 1 1
Centro Studi Fegato, Liver Research Center, Fondazione Italiana Fegato, Italian Liver Foundation, Italy 2 S.C. Laboratorio Analisi Cliniche, IRCCS Burlo Garofalo, Italy 3 Medical Research Institute, Area Science Park Basovizza, Bldg Q2, Italy 4 Department of Medical Sciences, University of Trieste, Trieste, Italy 5 Università degli Studi di Trieste, Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Italy Background and aims: NAFLD is a chronic liver disease without a specific therapy available. The aim of this work is to study the nutraceutical properties of Silimarin added to high fat diet in a NASH juvenile mice model. Materials and methods: Obese females and males 11 weeksold C57BL/6 mice, fed with High Fat High Carbohydrates Diet (HFHCD) during their whole life1, were exposed to Silimarin (1 mg/animal/day) added to HFHCD for further 12 weeks. Animals exposed only to HFHCD were used as control. Silimarin effects in vivo were assessed in terms of bodyweight, BMI, HOMA-IR, lipidemia, hepatomegaly, hypertrophy of visceral adipose tissue and liver histology. Moreover, the expression of profibrogenic genes was assess in the liver. Results: The addition of Silimarin to the HFHCD during the treatment period decreased the liver weight and the visceral fat (p < 0.001); it decreased also glycaemia (p < 0.05) but did not improve the HOMA-IR since insulin levels were unchanged. Plasmatic LDL-C, TG, ALT, AST were significantly reduced (p < 0.05). Histology of the liver showed a slight, but not significant, reduction in inflammatory foci and fibrosis. From a molecular point of view, Silmarin significantly decreased (p < 0.05) the expression of ␣-SMA (hepatic stellate activation marker) and Collagen 1A1 suggesting a potential effect in improving the fibrogenesis. Conclusions: Silimarin added to the HFHC diet might exert beneficial effects mainly improving lipidemia, liver damage and decreasing fibrogenesis. This data is particularly relevant to overcome patient compliance to change dietary habits. Funding: The present work was supported by MIUR (Art.13 D.LGS 297/99-Progetto Nutrizione e Salute) and by FIF in house grant. http://dx.doi.org/10.1016/j.dld.2015.07.028