The anti-anginal ranolazine does not confer beneficial actions against hepatic steatosis in male mice subjected to high-fat diet and streptozotocin-induced type 2 diabetes

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver in the absence of alcohol and increases one's risk for both diabetes and cardiovascular disease (e.g., angina). We have shown that the second-line anti-anginal therapy, ranolazine, mitigates obesity-induced NAFLD, and our aim was to determine whether these actions of ranolazine also extend to NAFLD associated with type 2 diabetes (T2D). Eight-week-old male C57BL/6J mice were fed either a low-fat diet or a high-fat diet for 15 weeks, with a single dose of streptozotocin (STZ; 75 mg/kg) administered in the high-fat diet-fed mice at 4 weeks to induce experimental T2D. Mice were treated with either vehicle control or ranolazine during the final 7 weeks (50 mg/kg once daily). We assessed glycemia via monitoring glucose tolerance, insulin tolerance, and pyruvate tolerance, whereas hepatic steatosis was assessed via quantifying triacylglycerol content. We observed that ranolazine did not improve glycemia in mice with experimental T2D, while also having no impact on hepatic triacylglycerol content. Therefore, the salutary actions of ranolazine against NAFLD may be limited to obese individuals but not those who are obese with T2D.