The Effects Of Ketogenic Diet On Lipid Metabolism In The Liver In Lipocalin 2 Knockout Mice

Abstract

Ketogenic diet is known to have benefits for epilepsy treatment and weight loss. However, long-term health outcomes of ketogenic diet remain debated. Lipocalin 2 (Lcn2) is a secreted protein known for its role in lipid metabolism by regulating mitochondrial function. In our previous studies, we observed that Lcn2 knockout (KO) mice had reduced levels of serum ketone bodies and increased liver lipid accumulation after receiving a long-term ketogenic diet feeding compared with wild-type (WT) mice. The current study was carried out to further investigate the role of Lcn2 in lipid metabolism in the liver under a long-term ketogenic diet feeding. We hypothesize that Lcn2 plays a crucial role in modulating the adverse effects of long-term ketogenic diet feeding on lipid accumulation in the liver. Specifically, we anticipate that Lcn2 deficiency will exacerbate hepatic lipid accumulation and impair ketogenesis in response to prolonged ketogenic diet consumption. Both Lcn2 KO mice and WT mice were examined after receiving either regular chow diet or ketogenic diet for 10 weeks. As liver is the principal site for ketogenesis, we examined the expression of genes involved in ketogenesis, mitochondrial fatty acid oxidation, lipogenesis, lipolysis, and oxidative stress to investigate how Lcn2 deficiency impacts the ketogenic diet-induced lipid metabolism in the liver. Our results showed that there was increased lipid accumulation and increased triglyceride levels in the liver in Lcn2 knockout mice fed a ketogenic diet for 10 weeks. In addition, the gene expression results indicate that the ketogenesis was altered and mitochondrial fatty acid oxidation was reduced in Lcn2 KO mice fed a ketogenic diet. Additionally, the results suggest that Lcn2 KO mice have reduced lipogenesis and increased lipolysis in the liver upon ketogenic diet feeding. Moreover, Lcn2 KO mice showed higher levels of oxidative stress in the liver under the ketogenic diet-fed condition compared with WT mice. In conclusion, Lcn2 deficiency impairs mitochondria function, which results in altered ketogenesis and reduced mitochondrial fatty acid oxidation capacity. Due to impaired mitochondrial function, Lcn2 deficiency leads to increased oxidative stress. Together, Lcn2 deficiency exacerbates the detrimental effects of long-term ketogenic diet on lipid metabolism in the liver, leading to fatty liver.