Cyclin D1 Represses Gluconeogenesis via Inhibition of the Transcriptional Coactivator PGC1α

Abstract

Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin D1 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1–mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator–activated receptor γ coactivator-1α (PGC1α) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC1α is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1α and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis.

The Proliferative Gene Cyclin D1 and Gluconeogenesis—Could Suppressing Glucose Production Also Promote Cancer?

“…It is difficult to assess this from the data presented by Bhalla et al (13) for the reasons discussed here. It is of interest that the lack of cyclin D1 can induce PEPCK and G6Pase, while overexpression elicits the opposite response.…”

A novel role for the cell cycle regulatory complex cyclin D1–CDK4 in gluconeogenesis

“…The mechanism responsible for the changes in the hepatic expression of cyclin D1 in response to fasting and refeeding observed by Bhalla et al 3. remains unclear.…”

“…Although the function of cyclin D1 in the liver has mostly been studied in the context of liver damage, regeneration, or carcinogenesis2, Bhalla et al 3. recently revealed that cyclin D1 represses hepatic gluconeogenesis and oxidative phosphorylation through inhibition of PGC1α activity in a CDK4‐dependent manner (Figure 1).…”

“…The liver‐specific cyclin D1 transgenic mice studied by Bhalla and coworkers3 develop hepatocellular carcinoma by an age of ~15 months. These researchers suggest that the regulation of PGC1α activity by cyclin D1–CDK4 might contribute to the molecular mechanism of the Warburg effect—the metabolism of glucose in cancer cells predominantly via glycolysis rather than via oxidative phosphorylation even in the presence of oxygen5.…”

“…The study of Bhalla et al 3. thus identifies cyclin D1–CDK4 as a potential target for the treatment of type 2 diabetes, although close attention will need to be paid to the potential carcinogenic effects of this cell cycle regulatory complex.…”