Co-regulation of Nr1d1 and Pparα in age-related changes of lipid metabolism and its modulation by calorie restriction.

Aging is associated with a decline in liver function, which increases the risk of age-related metabolic disorders. Calorie restriction (CR) counteracts age-related changes in the liver; however, the underlying molecular mechanism remains elusive. In this study, we integrated transcriptomic, bioinformatic, and molecular analyses to investigate the effects of aging and CR on age-related gene expression in the rat liver, focusing on the interplay between the circadian rhythm and lipid metabolism. Our results revealed aging-induced upregulation of Nr1d1, a key circadian repressor, and downregulation of Ppara, accompanied by decreased expression of fatty acid oxidation genes and increased expression of lipogenic genes. CR attenuated these age-related changes and restored circadian rhythm-related gene expression. Furthermore, we demonstrated that Nr1d1 overexpression inhibited PPARα binding to peroxisome proliferator response elements (PPRE), resulting in decreased fatty acid oxidation gene expression. Our findings suggest that age-related dysregulation of Nr1d1 contributes to impaired lipid metabolism in liver aging, and CR may exert its beneficial effects by modulating the interaction between NR1D1 and PPARα. This study provides novel insights into the molecular mechanisms linking circadian rhythms and lipid metabolism in hepatic aging.