BACKGROUND: Chronic overconsumption of high-fat diets contributes to obesity, with hyperlipidemia being a common comorbidity. The cardiovascular system is strongly influenced by diurnal rhythms, which regulate key functions such as endothelial activity, thrombosis, and blood pressure. Diurnal rhythms are central regulators of metabolic and physiological processes, and dietary pattern shifts can disrupt the synchronization of the internal clock within metabolic systems.
RESULTS: Using a hyperlipidemic mouse model, we investigated diurnal rhythm-related effects on the liver and intestine through transcriptomic, metagenomic, and metabolomic profiling. We identified several key genes-including CD36, Hmgcs1, Ehhadh, Cyp4a12b, Ifi27l2b, Ugt2b1, Ces2a, Cyp3a11, Selenbp2, and Gal3st1-that are regulated by the hepatic circadian clock and modulate metabolites via the gut-liver axis. The gut microbiota exhibited diurnal rhythmicity that coordinates intestinal digestion and metabolism, forming a synergistic circadian metabolic network. Hyperlipidemia disrupted normal circadian regulation in the liver and intestine, affecting lipid synthesis, transport, accumulation, and catabolism.
DISCUSSION: Our hepatic transcriptomic analysis revealed that a high-fat diet induces aberrant expression of lipid metabolism genes during the night. This diet also perturbs the diurnal rhythm of the gut microbiota, leading to intestinal metabolic dysregulation. Metabolites entering the portal circulation act as signaling molecules that bind to hepatic receptors and directly regulate the transcription of lipid metabolism genes. The loss of rhythmic metabolite secretion consequently disrupts circadian gene expression, contributing to hepatic lipid dysregulation via the gut-liver axis-a key mechanism in hyperlipidemia pathogenesis.
CONCLUSIONS: This study identifies critical temporal windows and core microbial taxa involved in microbiota-metabolite-gene crosstalk via the gut-liver axis, offering a theoretical foundation for diurnal rhythm-targeted interventions in metabolic diseases.
