Dietary α-Tocopherol Deficiency Disrupts Hepatic Circadian Clock and Lipid Metabolism in Association with Gut Microbiota Dysbiosis

Background/Objectives As a fat-soluble vitamin, vitamin E (VE) is prone to suboptimal intake in the general population. Alpha-tocopherol (α-TE) represents the most biologically significant form of VE in vivo. Nevertheless, the potential detrimental effects of α-TE deficiency on health remain unclear. This study was conducted to investigate the effect of α-TE deficiency on hepatic metabolism and gut microbiota. Methods C57BL/6J mice were randomly assigned to receive one of three dietary regimens: a α-TE-deficient diet, a control diet with normal α-TE, or a high-dose diet containing four times the normal α-TE level. Histopathology, serum biochemistry, RNA-Seq, RT-qPCR, Western blot, and 16S rRNA gene sequencing with correlation analysis were used to assess metabolic phenotypes, hepatic circadian, hepatic lipid metabolism, and cecal microbiota, respectively. Results The results demonstrated that α-TE deficiency induced hepatic steatosis and lipid metabolic disturbances. α-TE deficiency significantly decreased Arntl and Clock expression, but increased Per2. Additionally, it upregulated the expression of lipogenic genes such as Scd1, Elovl6, and Elovl3 and simultaneously downregulated fatty acid oxidation genes such as Cyp4a10, Cyp4a14, and Acot1, bringing about imbalance in lipid homeostasis. In addition, α-TE deficiency greatly changed the structure and composition of gut microbiota. Bacterial genera like Alistipes, norank_f__Muribaculaceae, Muribaculum, Odoribacter, and Dubosiella were significantly correlated with hepatic circadian and lipid metabolism gene expression with the strongest correlation being Alistipes. Conclusions This work is the first to reveal that short term α-TE deficiency could cause lipid metabolic disorder via the “gut microbiota–liver circadian clock” axis, which provides novel insights into the etiology of nutrition-related metabolic diseases and targets for nutritional intervention.