Ketones Increase ROS by Upregulating NADPH Oxidases in T1D Liver and Hepatocytes

The incidence of liver dysfunction is common in Type 1 diabetic (T1D) patients, but the mechanism is not well elucidated. There is no study that has examined whether hyperketonemia per se contributes to the progression of liver disease. T1D is associated with hyperketonemia, a condition with elevated blood levels of acetoacetate and 3‐β‐hydroxybutyrate coupled with hyperglycemia. This study investigates the hypothesis that ketones mediate the excess oxidative stress and cellular damage that can lead to impaired liver function using streptozotocin treated T1D rats and a hepatocyte cell (FL83B) model. We observed significant increases in NADPH oxidase 4 (NOX4), ROS, and ICAM‐1 levels in the livers of T1D rats, with a simultaneous elevation in blood ketones and liver dysfunction biomarkers (aspartate transaminase and alanine transaminase), in comparison with those seen in type 2 diabetic rats and controls. Cell culture studies show that ketones alone or in combination with high glucose treatment can cause a significant increase in NOX4, oxidative stress, and ICAM‐1 in hepatocytes. The upregulation of ICAM‐1, in vivo, can propagate the adhesion of neutrophils and macrophage infiltration into the liver leading to liver cell injury. This study provides evidence for a novel biochemical mechanism, in which NOX upregulation by ketones induces increased expression of ICAM‐1, thus elucidating the role of hyperketonemia per se in the excess injury seen in the liver in T1D. New drugs targeting the inhibition of NOX could provide better preventive approaches to reducing the risk of liver dysfunction associated with T1D. (Supported by NIH, the Malcolm Feist Chair in Diabetes, and a fellowship from the Malcolm Feist Cardiovascular Research Endowment, LSUHSC‐Shreveport)