Reversion of Steatosis by SREBP-1c Antisense Oligonucleotide did not Improve Hepatic Insulin Action in Diet-induced Obesity Mice

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The literature has associated hepatic insulin action with NAFLD. In this sense, treatments to revert steatosis and improve hepatic insulin action become important. Our group has demonstrated that inhibition of Sterol Regulatory Element Binding Proteins-1c (SREBP-1c) reverses hepatic steatosis. However, insulin signals after NAFLD reversion require better investigation. Thus, in this study, we investigated if the reversal of NAFLD by SREBP-1c inhibitor results in improvement in the hepatic insulin signal in obesity mice. After installation/achievement of diet-induced obesity and insulin resistance, Swiss mice were divided into 3 groups: i) Lean, ii) D-IHS, diet-induced hepatic steatosis [no treatment with antisense oligonucleotide (ASO)], and iii) RD-IHS, reversion of diet-induced hepatic steatosis (treated with ASO). The mice were treated with ASO SREBP-1c as previously described by our group. After ASO treatment, one set of animals was anesthetized and used for in vivo test, and another mice set was anesthetized and used for histology and Western blot analysis. Reversion of diet-induced hepatic steatosis did not change blood glucose, glucose decay constant (k(ITT)), body weight, or serum insulin levels. In addition, results showed that the protocol did not improve insulin pathway signaling, as confirmed by the absence of changes in IR, IRS1, Akt and Foxo1 phosphorylation in hepatic tissue. In parallel, no alterations were observed in proinflammatory molecules. Thus, our results suggest that the inhibition of SREBP-1c reverts steatosis, but without improving insulin hepatic resistance.4412885890Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Santa Catarina (FAPESC)Universidade do Extremo Sul Catarinense (UNESC)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Short-term inhibition of SREBP-1c expression reverses diet-induced non-alcoholic fatty liver disease in mice

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Objective. The present study investigates the level of Sterol-regulatory element-binding proteins (SREBP-1c) and related proteins in obese mice (DIO) treated with SREBP-1c antisense oligonucleotide (ASO) to observe a reversal of steatosis. Materials and methods. Swiss mice were fed on chow containing 61 kJ% saturated fat for 8 weeks to develop obesity. After this period, one group of animals was used to assess the molecular effects of SREBP-1c antisense oligonucleotide treatment by immunoblot analysis in a dose-response curve (0; 1.0; 2.0; 3.0; 4.0 nmol/day). After the dose (3.0 nmol/day) was determined, another group was treated for 14 days. After a period of 24 h following the last injection mice were killed and plasma and hepatic tissue were obtained to evaluate plasma triglycerides and total liver fat. Western blot was performed to evaluate SREBP-1c, FAS, SCD-1, PPAR gamma and CPT1 expression and AMPK[Thr172] and ACC[Ser79] phosphorylation. Livers were stained using the hematoxylin and eosin method for histological analysis. Results. Body weight, epididymal fat and glucose levels were not affected by one daily dose of ASO. However, total plasma triglycerides and total liver fat were significantly reduced. Also, this treatment inhibited SREBP-1c and reduced protein levels of a series of proteins involved in lipogenesis, including ACC, FAS and SCD-1. Moreover, mice treated with ASO presented a significant reduction in macroscopic and microscopic features of hepatic steatosis. Conclusion. Our results demonstrate that the inhibition of SREBP-1c decreased the expression of lipogenic enzymes, reducing the accumulation of triglycerides and, finally, reversing hepatic steatosis in mice.461113811388Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Santa Catarina (FAPESC) e Universidade do Extremo Sul Catarinense (UNESC)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Reversion of hepatic steatosis by exercise training in obese mice: The role of sterol regulatory element-binding protein-1c

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Aim: The dysregulation of regulatory element-binding protein-1c (SREBP-1c) is associated with hepatic steatosis. However, effects of exercise on SREBP-1c protein level in liver have not been investigated. Thus, in this study we investigated if reversion of the hepatic steatosis-induced by exercise training is related with levels of SREBP-1c. Main methods: Mice were divided into two groups: control lean mice (CT), fed on standard rodent chow, and obese mice (HF), fed on a high-fat diet for 2 months. After this period obese mice were divided in two groups: obese mice and obese mice submitted to exercise (HF + EXE). The HF + EXE group performed a running program of 50 min per day, 5 days per week, for 8 weeks. Forty-eight hours after the last exercise session, biochemical, immunoblotting, histology and immunohistochemistry analyses were performed. Key findings: Livers of HF mice showed increased SREBP-1c, FAS (Fatty Acid Synthase), SCD1 (Stearoyl-CoA Desaturase1) and CPT1 (Carnitine Palmitoyl Transferase1) protein levels (3.4, 5.0, 2.6 and 2.9 times, respectively), though ACC (Acetyl-CoA Carboxilase) phosphorylation dropped 4.2 times. In livers of HF + EXE, levels of SREBP-1c, FAS, SCDI and CPTI decreased 2.1, 1.9, 1.8, and 2.7 times, respectively), while ACC phosphorylation increased 3.0 times. Lower SREBP-1c protein levels after exercise were confirmed also by immunohistochemistry. Total liver lipids content was higher in HF (2.2 times) when compared to CT, and exercise training reduced it significantly (1.7 times). Significance: Our study allows concluding that the reduction in SREBP-1c protein levels is associated with steatosis reversion induced by exercise training. Crown Copyright (c) 2012 Published by Elsevier Inc. All rights reserved.9141984395401Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)University Southern of Santa Catarina (UNESC)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq