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Transcriptional regulation of hepatic lipogenesis

A Corrigendum to this article was published on 16 December 2015

Key Points

  • Lipogenic genes are coordinately regulated at the transcriptional level during the fasting–feeding cycle and by circadian rhythms.

  • Having common features at their promoter regions, lipogenic genes are coordinately regulated. 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.

  • Post-translational modifications of lipogenic transcription factors and co-regulators by hormones and nutrients are tightly regulated by several signalling pathways. Various kinases–phosphatases, including DNA-dependent protein kinase (DNA–PK), atypical protein kinase C (aPKC) and AKT–mTOR, and acetyltransferase–deacetylases such as p300, affect their function, stability and/or localization.

  • Chromatin remodelling by histone acetylation and methylation, as well as recruitment of the lipoBAF complex, have crucial roles in lipogenic gene transcription.

  • Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance. Furthermore, persistent lipogenesis during insulin resistance may occur, owing to nutrient fluxes to the liver.

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.

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Figure 1: Transcription factors, co-regulators and signalling pathways for hepatic lipogenic gene activation by insulin and glucose.
Figure 2: Modifications of upstream stimulatory factors (USFs) during the fasting–feeding cycle.
Figure 3: Transcription factors and co-regulators involved in the regulation of lipogenesis by circadian rhythms.

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Acknowledgements

Work in the authors' laboratory was supported by DK081098 (to H.S.S), and J.A.V. was supported by DK105671 from the US National institutes of Health.

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Correspondence to Hei Sook Sul.

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Glossary

Glycolysis

A series of enzyme-catalysed reactions that convert glucose into pyruvate.

Hyperlipidaemia

Abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.

Poly (ADP-ribose) polymerase 1

(PARP1). A nuclear protein, the main role of which is to detect and signal single-strand breaks (SSBs) in DNA to the enzymatic machinery involved in SSB repair. PARP1 activation is an immediate cellular response to metabolic, chemical or radiation-induced DNA SSB damage.

p300/CBP-associated factor

(PCAF; also known as lysine acetyltransferase 2B (KAT2B)). A transcriptional coactivator that has in vitro and in vivo binding activity with CREB-binding protein (CBP) and p300, and competes with E1A for binding sites in p300 and CBP. PCAF has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that it plays a direct part in transcriptional regulation.

ATP-binding cassette (ABC) transporters

Transmembrane proteins that utilize the energy from ATP binding and hydrolysis to carry out certain biological processes, including translocation of various substrates across membranes.

Peroxisome proliferator-activated receptor c co-activator 1α

(PGC1α). A transcriptional co-activator that is a central inducer of mitochondrial biogenesis in cells. PGC1α both increases mitochondrial functions and minimizes the build-up of their by-products, ensuring a global positive impact on oxidative metabolism.

Hypolipidaemia

Abnormally low levels of any or all lipids and/or lipoproteins in the blood.

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Wang, Y., Viscarra, J., Kim, SJ. et al. Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol 16, 678–689 (2015). https://doi.org/10.1038/nrm4074

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