Targeting lipogenesis in the treatment of metabolic diseases and cancer

Lipogenesis must be regulated tightly to meet metabolic needs according to nutritional status. During fasting, fatty acid synthesis is virtually absent mainly due to increased glucagon/cAMP signaling [1]. In contrast, during feeding, fatty acid synthesis mainly in liver increases drastically, especially when the diet is carbohydrate rich, as glucose utilization and glycolysis increase [2]. Increased levels of circulating glucose and insulin contribute to the induction of lipogenesis. Many enzymes involved in fatty acid and fat synthesis, including fatty acid synthase (FASN), ACC, SREBP1c, ACLY, and mitochondrial GPAT are upregulated at the transcriptional level in response to insulin signaling [3]. FASN plays a central role in de novo lipogenesis by catalyzing 7 reactions for palmitate synthesis from acetyl-CoA and malonyl-CoA, and is regulated at the transcriptional level during the fasting/feeding cycle [3]. Therefore, FASN makes an ideal target to study the transcriptional activation of lipogenesis. In understanding the transcriptional activation of FASN and other lipogenic genes by feeding/insulin, we have focused our efforts on upstream stimulatory factor 1 (USF1) and the signaling pathways involved [3, 4, 5]. While there are several transcription factors, such as SREBP1c, LXR, and ChREBP that are known to promote lipogenic gene transcription, we found that USF1 plays a central role as its binding to the -65 E-box is required for the activation of the FASN promoter by feeding/ insulin [3]. Furthermore, we have shown that multiple signaling pathways activated by insulin converge on USF1 and its coactivators in activating lipogenic genes during feeding/insulin treatment [3, 4]. Briefly, insulin causes PP1 translocation to the nucleus to dephosphorylate/ activate DNA-PK that, in turn, phosphorylates S262 of USF1. This is the first time that DNA-PK was shown to be a downstream kinase in insulin signaling. Thus, after being phosphorylated by DNA-PK, USF1 interacts with P/ CAF to be acetylated at K237. Phosphorylated/acetylated USF1 can then interact with BAF60c, which is itself phosphorylated at S247 by atypical PKC in response to insulin. The interaction between USF1 and BAF60c results in the recruitment of the LipoBAF complex to the FASN promoter for chromatin remodeling and transcriptional activation [3, 4]. Recently we identified Mediator complex subunit 17 (MED17) as a USF1 interacting protein which, by directly binding to USF1 recruits the Mediator complex to activate transcription following feeding/insulin treatment [5]. We determined that MED17 is phosphorylated at S53 by CK2 and that this phosphorylation is required for the activation Editorial