Dietary Conjugated Linoleic Acid Modulates the Hepatic Circadian Clock Program via PPARα/REV-ERBα-Mediated Chromatin Modification in Mice

Scope: Disruptions of circadian rhythm cause metabolic disorders and are closely related to dietary factors. In this study, we investigated the interplays between the dietary conjugated linoleic acid (CLA)-induced hepatic steatosis and the circadian clock regulation, in association with lipid homeostasis. Methods and Results: Exposure of mice to 1.5% dietary CLA for 28 days caused insulin resistance, enlarged livers, caused hepatic steatosis, and increased triglyceride levels. Transcriptional profiling showed that hepatic circadian clock genes were significantly downregulated with increased expression of the negative transcription factor, REV-ERB alpha. We uncovered that the nuclear receptor (NR) PPAR alpha, as a major target of dietary CLA, drives REV-ERB alpha expression via its binding to key genes of the circadian clock, including Cry1 and Clock, and the recruitment of histone marks and cofactors. The PPAR alpha or REV-ERB alpha inhibition blocked the physical connection of this NR pair, reduced the cobinding of PPAR alpha and REV-ERB alpha to the genomic DNA response element, and abolished histone modifications in the CLA-hepatocytes. In addition, we demonstrated that CLA promotes PPAR alpha driving REV-ERB alpha transcriptional activity by directly binding to the PPAR response element (PPRE) at the Nr1d1 gene. Conclusions: Our results add a layer to the understanding of the peripheral clock feedback loop, which involves the PPAR alpha-REV-ERB alpha, and provide guidance for nutrients optimization in circadian physiology.

Automated summary

This study investigated the interplays between dietary conjugated linoleic acid (CLA)-induced hepatic steatosis and circadian clock regulation, and found that PPAR alpha drives REV-ERB alpha expression by binding to key genes of the circadian clock. The results provide insights into the peripheral clock feedback loop and offer guidance for optimizing nutrients in circadian physiology.