Research Paper Advance Articles
Co-regulation of Nr1d1 and Pparα in age-related changes of lipid metabolism and its modulation by calorie restriction
- 1 Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
- 2 Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
- 3 Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Received: January 6, 2025 Accepted: June 24, 2025 Published: July 28, 2025
https://doi.org/10.18632/aging.206289How to Cite
Copyright: © 2025 Noh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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.
Abbreviations
Acaa1a: Acetyl-CoA Acyltransferase 1A; Acaca: Acetyl-CoA Carboxylase Alpha; Acly: ATP Citrate Lyase; ANOVA: Analysis of Variance; Bmal1: Brain and Muscle ARNT-Like 1; BP: Biological Processes; CC: Cellular Components; Clock: Circadian Locomotor Output Cycles Kaput; Cpt2: Carnitine Palmitoyltransferase 2; CR: Calorie Restriction; Cry1/2: Cryptochrome 1/2; Cyp4a1: Cytochrome P450 4A1; DAVID: Database for Annotation, Visualization, and Integrated Discovery; DEGs: Differentially Expressed Genes; DMEM: Dulbecco’s Modified Eagle Medium; ECM: Extracellular Matrix; Fasn: Fatty Acid Synthase; FBS: Fetal Bovine Serum; GO: Gene Ontology; HRP: Horseradish Peroxidase; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAFLD: Metabolic Dysfunction-Associated Fatty Liver Disease; MF: Molecular Functions; Nfil3: Nuclear Factor, Interleukin 3 Regulated; NR1D1: Nuclear Receptor Subfamily 1 Group D Member 1; OE: Overexpression; PBS: Phosphate-Buffered Saline; Per1/2: Period 1/2; PPI: Protein-Protein Interaction; PPAR: Peroxisome Proliferator-Activated Receptor; PPARα: Peroxisome Proliferator-Activated Receptor alpha; Ppard: Peroxisome Proliferator Activated Receptor Delta; PPRE: Peroxisome Proliferator Response Elements; qRT-PCR: quantitative Real-Time Polymerase Chain Reaction; RNA-seq: RNA sequencing; Rora: RAR Related Orphan Receptor A; Rorc: RAR Related Orphan Receptor C; RWR: Random Walk with Restart; Scd: Stearoyl-CoA Desaturase; SD: Sprague Dawley; SDS-PAGE: Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis; SEM: Standard Error of the Mean; STRING: Search Tool for the Retrieval of Interacting Genes/Proteins; TG: Triglycerides.