Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1.

@article{Zhao2012RegulationOL,
  title={Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1.},
  author={Xiaoping Zhao and Daorong Feng and Qun Wang and Arian Abdulla and Xiao-Jun Xie and Jie Zhou and Yan Lindsay Sun and Ellen S T Yang and Lu-ping Liu and Bhavapriya Vaitheesvaran and Lauren Bridges and Irwin J. Kurland and Randy Strich and Jianquan Ni and Chenguang Wang and Johan Ericsson and Jeffrey E. Pessin and Jun-Yuan Ji and Fajun Yang},
  journal={The Journal of clinical investigation},
  year={2012},
  volume={122 7},
  pages={
          2417-27
        }
}
Altered lipid metabolism underlies several major human diseases, including obesity and type 2 diabetes. However, lipid metabolism pathophysiology remains poorly understood at the molecular level. Insulin is the primary stimulator of hepatic lipogenesis through activation of the SREBP-1c transcription factor. Here we identified cyclin-dependent kinase 8 (CDK8) and its regulatory partner cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes, and… 

Figures from this paper

mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC)

TLDR
The results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression.

The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1

TLDR
It is shown in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing and regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.

Insulin-induced de novo lipid synthesis occurs mainly via mTOR-dependent regulation of proteostasis of SREBP-1c

Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although

Phosphorylation dependent proteostasis of sterol regulatory element binding proteins.

PIASy-Mediated Sumoylation of SREBP1c Regulates Hepatic Lipid Metabolism upon Fasting Signaling

TLDR
It is demonstrated that the small ubiquitin-related modifier (SUMO) E3 ligase, a protein inhibitor of activated STAT Y (PIASy), sumoylates SREBP1c at Lys98, leading to suppression of the hepatic lipogenic program upon fasting-induced signals, suggesting that PKA-induced SRE BP1c sumoylation by PIASy is a key regulatory mechanism to turn off hepaticlipogenesis during nutritional deprivation.

Regulation of Lipogenic Gene Expression by Lysine-specific Histone Demethylase-1 (LSD1)*

TLDR
Results show that LSD1 plays a role in regulating lipogenic gene expression, suggesting LSD1 as a potential target for treating dysregulation of lipid metabolism.

Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP.

TLDR
The authors attempt to summarize the current understanding of the molecular mechanism for the transcriptional regulation of hepatic lipogenesis, focusing on recent studies that explore the signaling pathways controlling SREBPs and ChREBP.

Inhibition of SREBP Transcriptional Activity by a Boron-Containing Compound Improves Lipid Homeostasis in Diet-Induced Obesity

TLDR
Results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.

SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism

TLDR
The results indicate that SREBP1 had important role in tumor progression and appears to be a novel prognostic marker for pancreatic cancer.

Lipogenic SREBP-1a/c transcription factors activate expression of the iron regulator hepcidin, revealing cross-talk between lipid and iron metabolisms

TLDR
Results indicate that the SREBP-1a/c transcription regulators activate hepcidin expression and thereby contribute to the control of mammalian iron metabolism.
...

References

SHOWING 1-10 OF 61 REFERENCES

The Role of SREBP-1c in Nutritional Regulation of Lipogenic Enzyme Gene Expression*

TLDR
It is found that SREBP-1c overexpression leads to a modest induction of fatty acid synthase, S14, and acetyl-CoA carboxylase mRNAs, which is not sufficient for the induction seen when hepatocytes are treated with insulin and high glucose.

SREBP-1c Transcription Factor and Lipid Homeostasis: Clinical Perspective

TLDR
A role for SREBP-1c in dyslipidaemia and type 2 diabetes has been considered in genetic studies and some association demonstrated, and it could also participate to the hepatic steatosis observed in humans and related to alcohol consumption and hyperhomocysteinaemia.

A Phosphorylation Cascade Controls the Degradation of Active SREBP1*

TLDR
The degradation of mature SREBP1 is controlled by cross-talk between multiple phosphorylated residues in its C-terminal domain and the phosphorylation of Ser-434 could function as a molecular switch to control these processes.

Sterol Regulatory Element-binding Protein-1 as a Key Transcription Factor for Nutritional Induction of Lipogenic Enzyme Genes*

TLDR
It is demonstrated that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.

Dysregulation of CDK8 and Cyclin C in tumorigenesis.

  • Wu XuJ. Ji
  • Biology
    Journal of genetics and genomics = Yi chuan xue bao
  • 2011

Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle.

TLDR
Promoter analysis showed that different combinations of transcription factor binding sites around the SRE binding motifs may determine regulatory networks of transcription that could explain the superposition of lipid and cholesterol metabolism with various other pathways involved in adaptive responses to stress like hypoxia and heat shock, or involvement in the immune response.

Insulin Enhances the Biogenesis of Nuclear Sterol Regulatory Element-binding Protein (SREBP)-1c by Posttranscriptional Down-regulation of Insig-2A and Its Dissociation from SREBP Cleavage-activating Protein (SCAP)·SREBP-1c Complex*

TLDR
It is reported here that insulin persistently stimulates controlled proteolysis of the nascent SREBP-1c by selectively reducing the level of Insig-2a protein via accelerated degradation of its cognate mRNA.

Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription.

TLDR
Evidence is provided for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS).

Liver-specific mRNA for Insig-2 down-regulated by insulin: Implications for fatty acid synthesis

TLDR
A liver-specific transcript of Insig-2 is reported, which is the predominant transcript in livers of fed animals, and it is selectively down-regulated by insulin, thereby allowing insulin to stimulate fatty acid synthesis, even under conditions in which hepatic cholesterol levels are elevated.
...