title: Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation.
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.
authors.affiliation: Gastroenterology Division, Minneapolis VA Health Care System, Minneapolis, MN 55417, USA.
authors.forename: Sushama
authors.initials: S
authors.lastname: Kamarajugadda
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, 55404, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Becker
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, 55404, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hanse
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mashek
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Mara T
authors.initials: MT
authors.lastname: Mashek
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, 55404, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hendrickson
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, 55404, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Mullany
authors.affiliation: Gastroenterology Division, Minneapolis VA Health Care System, Minneapolis, MN 55417, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Albrecht
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D005227:Fatty Acids; C000715470:MAS1 protein, human; D047493:PPAR alpha; D000090063:Proto-Oncogene Mas; D019938:Cyclin D1
keywords: breast cancer; hepatocellular carcinoma; liver regeneration; metabolism; peroxisome proliferator-activated receptor alpha