Oral formulation of angiotensin-(1-7) improves lipid metabolism and prevents high-fat diet-induced hepatic steatosis and inflammation in mice.

Angiotensin (Ang)-(1-7) has been described as an important tool on treating and preventing metabolic disorders. In this study, we aimed to evaluate the effect of an oral formulation of Ang-(1-7) included in hydroxypropylß-cyclodextrin (HPßCD/Ang-[1-7]) on hepatic function, steatosis, and on liver inflammatory markers expression in mice treated with a high-fat diet. Male FVB/N mice were divided into 4 groups and fed for 60 days, with each group receiving 1 of the following diets: standard diet+HPßCD, standard diet+Ang-(1-7)/HPßCD, high-fat diet+HPßCD, or high-fat diet+Ang-[1-7]/HPßCD. Body weight, food intake, and blood parameters, such as total cholesterol, triglyceride, alaninetransaminases, and aspartate transaminases, were evaluated. Immunohistochemical analyses were performed for inflammatory markers tumor necrosis factor-α and interleukin-6. Expression of angiotensin converting enzyme, angiotensin-converting enzyme-2, interleukin-1ß, tumor necrosis factor-α, interleukin-6, transforming growth factor-ß, acetyl-CoA carboxylase, carbohydrate-responsive element-binding protein, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins-1c was evaluated by quantitative real-time polymerase chain reaction. The major findings of our study included reduced liver fat mass and weight, decreased plasma total cholesterol, triglyceride, and alaninetransaminase enzyme levels in the oral Ang-(1-7)-treated groups compared with the control groups. These results were accompanied by a significant reduction in tumor necrosis factor-α and interleukin-6 mRNA expression in the liver. Analyses of liver adipogenesis-related genes by quantitative real-time polymerase chain reaction showed that acetyl-CoA carboxylase, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins-1c mRNA expression were significantly suppressed. In conclusion, we observed that treatment with Ang-(1-7) improved metabolism and decreased proinflammatory profile and fat deposition in liver of mice.

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

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 2months. 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 50min per day, 5days per week, for 8weeks. 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.

Srebf1a is a key regulator of transcriptional control for adipogenesis.

Adipogenesis is regulated by a complex cascade of transcriptional factors, but little is known about the early events that regulate the adipogenic program. Here, we report the role of the srebf1a gene in the differentiation of fibroblastic 3T3-F442A cells. We found that expression of srebf1a depended on GSK3ß activity and that GSK3ß activity was necessary for C/EBPß phosphorylation at Thr188. Knockdown of srebf1a inhibited the adipogenic program because it blocked the expression of genes encoding PPARγ2, C/EBPα, SREBP1c and even FABP4, demonstrating that SREBP1a activation is upstream of these three essential adipogenic transcription factors. Kinetic analysis during differentiation illustrated that the order of expression of adipogenic genes was the following: cebpb, srebf1a, pparg2, cebpa, srebp1c and fabp4. Our data suggest that srebf1a acts as an essential link between the GSK3ß-C/EBPß signaling axis and the beginning of the adipogenic transcriptional cascade.

Regulation of Triglyceride Metabolism. II. Function of mitochondrial GPAT1 in the regulation of triacylglycerol biosynthesis and insulin action.

GPAT1, one of four known glycerol-3-phosphate acyltransferase isoforms, is located on the mitochondrial outer membrane, allowing reciprocal regulation with carnitine palmitoyltransferase-1. GPAT1 is upregulated transcriptionally by insulin and SREBP-1c and downregulated acutely by AMP-activated protein kinase, consistent with a role in triacylglycerol synthesis. Knockout and overexpression studies suggest that GPAT1 is critical for the development of hepatic steatosis and that steatosis initiated by overexpression of GPAT1 causes hepatic, and perhaps also peripheral, insulin resistance. Future questions include the function of GPAT1 in relation to the other GPAT isoforms and whether the lipid intermediates synthesized by GPAT and downstream enzymes in the pathway of glycerolipid biosynthesis participate in intracellular signaling pathways.