Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4α

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.

Molecular ties between the cell cycle and differentiation in embryonic stem cells

“…Indeed, many terminal cell systems couple cell cycle inhibition with differentiation (1), and many potent transcription factors interact with cell cycle components in ways similar to MyoD, including Ngn2, Pdx1, Smad3, Mitf, Runx2, PU.1, Hnf4α, and C/EBPβ (17)(18)(19)(20)(21)(22)(23)(24). Whereas experimental validation and extension of our findings with MyoD to other lineages remains to be Fig.…”

Cdks, cyclins and CKIs: roles beyond cell cycle regulation

“…It was reported that Cdk8/cyclin C-dependent phosphorylation of Srebp-1c blocked the lipogenic pathway by targeting Srebp-1c for ubiquitin-mediated degradation (Zhao et al, 2012). Cyclin D1 also inhibits hepatic lipogenesis but its effects were mediated through the repression of two other transcription factors involved in the expression of lipogenic genes: carbohydrate response element-binding protein (ChREBP; Mlxipl) and hepatocyte nuclear factor 4α (Hnf4α) (Hanse et al, 2012). It is tempting to speculate that cell cycle regulators limit the conversion of glucose to lipids for storage so that energy resources can be reallocated to meet the increased demands during cell proliferation.…”

Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration

“…1C). Finally, we measured the levels of the cell cycle regulator CYCLIN D1, a well-established regulator of cell growth known to be up-regulated during liver regeneration (28,29). The induction of CYCLIN D1 expression was significantly decreased in SULF2-KO mice at 36 and 48 h after PH (Fig.…”