Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation.

Sushama Kamarajugadda,Jeffrey H Albrecht,Anna M Hendrickson,Eric A Hanse,Lisa K Mullany,Mara T Mashek,Jennifer R Becker,Douglas G Mashek

doi:10.18632/oncotarget.10274

Sushama Kamarajugadda, Jeffrey H Albrecht + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.10274

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Abstract

Cyclin D1 is a cell cycle protein that promotes proliferation by mediating progression through key checkpoints in G1 phase. It is also a proto-oncogene that is commonly overexpressed in human cancers. In addition to its canonical role in controlling cell cycle progression, cyclin D1 affects other aspects of cell physiology, in part through transcriptional regulation. In this study, we find that cyclin D1 inhibits the activity of a key metabolic transcription factor, peroxisome proliferator-activated receptor α (PPARα), a member of nuclear receptor family that induces fatty acid oxidation and may play an anti-neoplastic role. In primary hepatocytes, cyclin D1 inhibits PPARα transcriptional activity and target gene expression in a cdk4-independent manner. In liver and breast cancer cells, knockdown of cyclin D1 leads to increased PPARα transcriptional activity, expression of PPARα target genes, and fatty acid oxidation. Similarly, cyclin D1 depletion enhances binding of PPARα to target sequences by chromatin immunoprecipitation. In proliferating hepatocytes and regenerating liver in vivo, induction of endogenous cyclin D1 is associated with diminished PPARα activity. Cyclin D1 expression is both necessary and sufficient for growth factor-mediated repression of fatty acid oxidation in proliferating hepatocytes. These studies indicate that in addition to playing a pivotal role in cell cycle progression, cyclin D1 represses PPARα activity and inhibits fatty acid oxidation. Our findings establish a new link between cyclin D1 and metabolism in both tumor cells and physiologic hepatocyte proliferation.

Highlights

During the processes of proliferation and growth, cells undergo marked shifts in metabolism in order to provide for the synthesis of new cellular components, energy production, and maintenance of cellular redox balance
We find that cyclin D1 inhibits the activity of a key metabolic transcription factor, peroxisome proliferatoractivated receptor α (PPARα), a member of nuclear receptor family that induces fatty acid oxidation and may play an anti-neoplastic role
Hepatocytes were cultured at high density in the presence of a relatively low concentration of glucose (5.5 mM) [18], which activates the expression of PPARα target genes

Summary

Introduction

During the processes of proliferation and growth, cells undergo marked shifts in metabolism in order to provide for the synthesis of new cellular components, energy production, and maintenance of cellular redox balance. These changes typically include increased utilization of glucose and glutamine and decreased oxidative phosphorylation. The full spectrum and regulation of metabolic changes seen in proliferation and malignancy are incompletely understood. During the process of www.impactjournals.com/oncotarget compensatory hepatocyte proliferation and growth, the metabolic function of the liver is altered to accommodate the synthetic and energetic demands of these processes [6, 7]. The mechanisms underlying the adaptations in hepatic metabolism during liver regeneration are poorly understood, but include changes in the systemic hormonal milieu and regulation of key metabolic transcription factors including the nuclear receptors hepatocyte nuclear factor 4α (HNF4α) and NR1H4 (FXR)

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