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Nr1d1和Pparα在脂质代谢年龄相关变化中的共同调节及其受卡路里限制的调控

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

作者信息

Noh Sang Gyun, Kim Hyun Woo, Kim Seungwoo, Yu Byung Pal, Yoon Jeong-Hyun, Chung Ki Wung, Lee Jaewon, Chung Hae Young

机构信息

Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea.

Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.

出版信息

Aging (Albany NY). 2025 Jul 28;17(7):1810-1833. doi: 10.18632/aging.206289.

DOI:10.18632/aging.206289
PMID:40728518
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12339034/
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 , a key circadian repressor, and downregulation of , 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 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 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.

摘要

衰老与肝功能下降相关，这增加了与年龄相关的代谢紊乱风险。热量限制（CR）可抵消肝脏中与年龄相关的变化；然而，其潜在的分子机制仍不清楚。在本研究中，我们整合了转录组学、生物信息学和分子分析，以研究衰老和CR对大鼠肝脏中与年龄相关基因表达的影响，重点关注昼夜节律与脂质代谢之间的相互作用。我们的结果显示，衰老诱导关键昼夜节律抑制因子的上调以及的下调，同时伴随着脂肪酸氧化基因表达的降低和脂肪生成基因表达的增加。CR减弱了这些与年龄相关的变化，并恢复了与昼夜节律相关的基因表达。此外，我们证明过表达抑制PPARα与过氧化物酶体增殖物反应元件（PPRE）的结合，导致脂肪酸氧化基因表达降低。我们的研究结果表明，与年龄相关的失调导致肝脏衰老中脂质代谢受损，CR可能通过调节NR1D1与PPARα之间的相互作用发挥其有益作用。本研究为肝脏衰老中昼夜节律与脂质代谢之间的分子机制提供了新的见解。

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