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Research Paper|Volume 17, Issue 7|pp 1810—1833

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

Sang Gyun Noh1, Hyun Woo Kim1, Seungwoo Kim2, Byung Pal Yu3, Jeong-Hyun Yoon1,2, Ki Wung Chung1,2, Jaewon Lee1,2, Hae Young Chung1,2
  • 1Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea
  • 2Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
  • 3Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Received: January 6, 2025Accepted: June 24, 2025Published: July 28, 2025
https://doi.org/10.18632/aging.206289

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.