enalapril and Non-alcoholic-Fatty-Liver-Disease

We examined whether reversal of high fat diet, stimulating weight loss, compared to two treatments previously shown to have beneficial effects, could improve glucose utilization and peripheral neuropathy in animal models of obesity and type 2 diabetes. Rats were fed a high fat diet and treated with a low dose of streptozotocin to create models of diet induced obesity or type 2 diabetes, respectively. Afterwards, rats were transferred to a normal diet or treated with enalapril or dietary enrichment with menhaden oil for 12 weeks. Obesity and to a greater extent type 2 diabetes were associated with impaired glucose utilization and peripheral neuropathy. Placing obese rats on a normal diet improved glucose utilization. Steatosis but not peripheral neuropathy was improved after placing obese or diabetic rats on a normal diet. Treating obese and diabetic rats with enalapril or a menhaden oil enriched diet generally improved peripheral neuropathy endpoints. In summary, dietary improvement with weight loss in obese or type 2 diabetic rats was not sufficient to correct peripheral neuropathy. These results further stress the need for discovery of a comprehensive treatment for peripheral neuropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Obesity Agents; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diet, Fat-Restricted; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Enalapril; Fish Oils; Hypoglycemic Agents; Male; Neuralgia; Non-alcoholic Fatty Liver Disease; Obesity; Rats, Sprague-Dawley; Streptozocin; Weight Loss

The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD).. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test.. All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS).. Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.

Topics: Adipose Tissue; Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Enalapril; Fumarates; Gene Expression Profiling; Gene Expression Regulation; Gluconeogenesis; Insulin Resistance; Leptin; Lipid Metabolism; Losartan; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Renin-Angiotensin System