Transcriptional regulation of hepatic lipogenesis - PubMed (original) (raw)
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Transcriptional regulation of hepatic lipogenesis
Yuhui Wang et al. Nat Rev Mol Cell Biol. 2015 Nov.
Erratum in
- Nat Rev Mol Cell Biol. 2016 Jan;17(1):64
Abstract
Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT-mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.
Figures
Figure 1
Transcription factors and coregulators and the signalling pathways for hepatic lipogenic gene activation by insulin and glucose Signaling and transcription network for activation of hepatic lipogenesis. Insulin signaling and glucose uptake trigger activation of series of kinases downstsream of PI3K, such as Akt, aPKC (PKC λ/⎛), mTORC1/2, DNA-PK, as well as phosphatases, such as PP1 and PP2. These kinases and phosphotases modify transcription factors by phosphorylation or dephosphorylation, respectively. Activated transcription factors, including USF-1, SREBP-1c, ChREBP and LXR, are bound to lipogenic gene promoter regions at E-box, SRE, ChoRE and LXRE, respectively, for transcriptional activation. USF-1 also recruits lipoBAF complex leading to chromatin remodeling for transcription.
Figure 2
Modifications of USF during the fasting and feeding transition. In fasting, USF is deacetylated by HDAC9. Upon feeding, USF is phosphorylated by DNA-PK and subsequently acetylated by P/CAF. Phosphorylated acetylated USF interacts with BAF60c for recruitment of the LipoBAF Complex.
Figure 3
Transcription factors and coregulators involved in the regulation of lipogenesis by circadian rhythm. During the light time, Rev-erbα/β binds to RORE and recruits HDAC3 and NCoR to inhibit lipogenesis in rodents. ROR competitively binds to the same region as Rev-erbα/β at night to activate lipogenesis.
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