Role of Hyperketonemia in Inducing Oxidative Stress and Cellular Damage in Cultured Hepatocytes and Type 1 Diabetic Rat Liver.

Type 1 diabetic (T1D) patients have a higher incidence of liver disease. T1D patients frequently experience elevated plasma ketone levels along with hyperglycemia. However, no study has examined whether hyperketonemia per se has any role in excess liver damage in T1D. This study investigates the hypothesis that hyperketonemia can induce oxidative stress and cellular dysfunction. STZ treated diabetic rats, FL83B hepatocytes, and GCLC knocked down (GSH deficient) hepatocytes were used. The blood levels of ALT and AST, biomarkers of liver damage, and ketones were elevated in T1D rats. An increase in NOX4 and ROS along with a reduction in GSH and GCLC levels was observed in T1D rat livers in comparison to those seen in non-diabetic control or type 2 diabetic rats. MCP-1 and ICAM-1 were also elevated in T1D rat livers and ketone treated hepatocytes. Macrophage markers CCR2 and CD11A that interact with MCP-1, and ICAM-1 respectively, were also elevated in the T1D liver, indicating macrophage infiltration. Additionally, activated macrophages increased hepatocyte damage with ketone treatment, which was similar to that seen in GCLC knockdown hepatocytes without ketones. Hyperketonemia per se can induce macrophage mediated damage to hepatocytes and the liver, caused by GSH depletion and oxidative stress up regulation in T1D.