Long-Term Casein-Bound Lactulosyllysine Consumption Induced Nonobese Nonalcoholic Fatty Liver Disease by Promoting Carbonyl Glycation in the Liver of C57BL/6 Mice

Lactulosyllysine (LL) is abundant in thermally processed dairy products, with its concentration increasing in response to more intense heat treatment. However, there are limited studies on the potential harmful effects of LL on human health. This study investigated the negative impact of casein-bound LL on liver health by feeding healthy C57BL/6 mice diets containing varying levels of casein-bound LL. After 16 weeks of LL diet administration, mice exhibited a nonobese nonalcoholic fatty liver disease (NONAFLD) phenotype, characterized by reduced body weight gain, hypolipidemia, and intrahepatic lipid accumulation. Nontarget metabolomic analysis showed that casein-bound LL induced alterations in plasma levels of compounds associated with lipid degradation. Mechanistically, casein-bound LL may impair the function of 5'-adenosine monophosphate-activated protein kinase and apolipoprotein B100 by inducing dicarbonyl stress, thereby promoting carbonyl glycation in the liver. Consequently, the long-term consumption of LL-rich dairy products may be a contributing factor to the risk of developing NONAFLD.