Abstract
Following acute hepatic injury, the metabolic capacity of the liver is altered during the process of compensatory hepatocyte proliferation by undefined mechanisms. In this study, we examined the regulation of de novo lipogenesis by cyclin D1, a key mediator of hepatocyte cell cycle progression. In primary hepatocytes, cyclin D1 significantly impaired lipogenesis in response to glucose stimulation. Cyclin D1 inhibited the glucose-mediated induction of key lipogenic genes, and similar effects were seen using a mutant (D1-KE) that does not activate cdk4 or induce cell cycle progression. Cyclin D1 (but not D1-KE) inhibited the activity of the carbohydrate response element-binding protein (ChREBP) by regulating the glucose-sensing motif of this transcription factor. Because changes in ChREBP activity could not fully explain the effect of cyclin D1, we examined hepatocyte nuclear factor 4α (HNF4α), which regulates numerous differentiated functions in the liver including lipid metabolism. We found that both cyclins D1 and D1-KE bound to HNF4α and significantly inhibited its recruitment to the promoter region of lipogenic genes in hepatocytes. Conversely, knockdown of cyclin D1 in the AML12 hepatocyte cell line promoted HNF4α activity and lipogenesis. In mouse liver, HNF4α bound to a central domain of cyclin D1 involved in transcriptional repression. Cyclin D1 inhibited lipogenic gene expression in the liver following carbohydrate feeding. Similar findings were observed in the setting of physiologic cyclin D1 expression in the regenerating liver. In conclusion, these studies demonstrate that cyclin D1 represses ChREBP and HNF4α function in hepatocytes via Cdk4-dependent and -independent mechanisms. These findings provide a direct link between the cell cycle machinery and the transcriptional control of metabolic function of the liver.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2681-2690 |
| Number of pages | 10 |
| Journal | Cell Cycle |
| Volume | 11 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2012 |
Bibliographical note
Funding Information:cyclin D1 may also regulate components of the insulin-signaling The authors thank Frances Sladek for the HNF4α reporter plas-pathway. In addition to its effect on lipid metabolism, we have mids and Eric Knudsen for the cyclin D1b antibody. This work recently found that cyclin D1 regulates estrogen and androgen was supported by NIH Grants DK54921(J.H.A.), F32DK074320 metabolism in the liver,34 and gene array data suggest that it may (L.K.M.) and DK085008 (D.G.M.) and American Diabetes impact other aspects of hepatic function in vivo.22 It is therefore Association grant 07-07-JF-43 (D.G.M.). plausible that cyclin D1 has diverse metabolic effects in the liver and other tissues. Our finding that cyclin D1 inhibits HNF4α activity could have implications for normal and malignant cell cycle progression
Keywords
- Cell cycle
- Cyclin D1
- Cyclins
- Hepatocyte nuclear factor 4 alpha
- Lipid metabolism
- Lipogenesis
- Liver regeneration