Phosphorylation and Recruitment of BAF60c in Chromatin Remodeling for Lipogenesis in Response to Insulin

Wang, Yuhui; Wong, Roger Hoi-Fung; Tang, Tsung-Ta; Hudak, Carolyn S.; Yang, Daizhi; Duncan, Robin E.; Sul, Hei Sook

doi:10.1016/j.molcel.2012.10.028

Cited by 65 publications

(81 citation statements)

References 40 publications

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“…While low endonuclease accessibility of the FAS and mGPAT promoter regions is observed in serum starvation, the endonuclease accessibility is remarkably increased upon insulin treatment. These observations demonstrate altered chromatin structure of lipogenic promoter regions during fasting-feeding cycle 102 . Two highly conserved mechanisms underlie the alteration of chromosome structure: 1) Posttranslational modification of histones, and 2) ATP-dependent chromosome remodeling.…”

Section: Chromatin Remodeling For Lipogenic Gene Transcriptionmentioning

confidence: 63%

Transcriptional regulation of hepatic lipogenesis

Wang

Viscarra

Kim

et al. 2015

Nat Rev Mol Cell Biol

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544

433

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Fatty acid and fat synthesis in liver is a highly regulated metabolic pathway critical for energy distribution. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcription level. Transcription factors, such as USF, SREBP-1c, LXR and ChREBP play critical roles in this process. Recently, insights have been gained into how various signaling pathways regulate these transcription factors. After feeding, high blood glucose and insulin induce lipogenic genes through several pathways, including DNA-PK, aPKC and Akt-mTOR. Various transcription factors and coregulators undergo specific modifications, such as phosphorylation, acetylation, or ubiquitination, which affect their function, stability, or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.

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Section: Chromatin Remodeling For Lipogenic Gene Transcriptionmentioning

confidence: 63%

Transcriptional regulation of hepatic lipogenesis

Wang

Viscarra

Kim

et al. 2015

Nat Rev Mol Cell Biol

Self Cite

544

433

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“…For example, the expression of SREBP1c is promoted by feeding via insulin and/or glucose in liver and fat tissues (12)(13)(14). Insulin, a key anabolic hormone, stimulates the expression and activity of SREBP1c through the phosphoinositol-3-kinase (PI3K)-and mammalian target of rapamycin complex 1 (mTORC1)-dependent pathways to mediate insulin action (14)(15)(16)(17)(18)(19)(20). Subsequently, activated SREBP1c potentiates most lipogenic genes, including those for fatty acid synthase (FASN), stearoyl coenzyme A (stearoyl-CoA) desaturase 1 (SCD1), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL), to induce de novo lipogenesis for the storage of a future energy source (21,22).…”

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confidence: 99%

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

Lee

Jang

Lee

et al. 2014

Molecular and Cellular Biology

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e SREBP1c is a key transcription factor that regulates de novo lipogenesis during anabolic periods. However, the molecular mechanisms involved in the suppression of SREBP1c under nutritional deprivation are largely unknown. In this study, we demonstrate 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. In primary hepatocytes, ablation of PIASy stimulated intracellular lipid accumulation through the induction of SREBP1c and its target genes. Given that protein kinase A (PKA) plays important roles in catabolic responses, activated PKA enhances the sumoylation of SREBP1c and potentiates the interaction between SREBP1c and PIASy. Notably, overexpression of PIASy in obese db/db mice ameliorated hepatic steatosis, while suppression of PIASy in lean (wild-type) mice stimulated hepatic lipogenesis with increased expression of SREBP1c target genes. Furthermore, PKA-mediated SREBP1c phosphorylation augmented SREBP1c sumoylation, subsequently leading to degradation of SREBP1c via ubiquitination. Together, these data suggest that PKA-induced SREBP1c sumoylation by PIASy is a key regulatory mechanism to turn off hepatic lipogenesis during nutritional deprivation.

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“…In this regard, note that both aPKC-phosphorylated/activated Brg1/Brm-associated factor-60C (BAF60c) and Akt- or other kinase-stimulated mTORC1 participate in SREBP-1c-dependent hepatic lipogenic enzyme expression (12–18). Also note that, although the elevation of mTOR phosphorylation in the face of diminished Akt activity may be surprising, it suggests that a modicum of Akt is sufficient, or factors other than Akt can increase mTOR phosphorylation in livers of obese and T2D humans, e.g., aPKC or other PKCs reportedly activate mTOR and/or p70/S6kinase (36, 37).…”

Section: Discussionmentioning

confidence: 99%

BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans

2015

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Information on insulin resistance in human liver is limited. In mouse diet-induced obesity (DIO), hepatic insulin resistance initially involves: lipid + insulin-induced activation of atypical protein kinase C (aPKC); elevated Akt activity/activation but selective impairment of compartmentalized Akt-dependent FoxO1 phosphorylation; and increases in gluconeogenic and lipogenic enzymes. In advanced stages, e.g., in hepatocytes of type 2 diabetes (T2D) humans, insulin activation of insulin receptor substrate-1(IRS-1) and Akt fails, further increasing FoxO1-dependent gluconeogenic/lipogenic enzyme expression. Increases in hepatic PGC-1α also figure prominently, but uncertainly, in this scheme. Here, we examined signaling factors in liver samples harvested from human transplant donors with increasing BMI, 20→25→30→35→40→45. We found, relative to lean (BMI=20–25) humans, obese (BMI>30) humans had all abnormalities seen in early mouse DIO, but, surprisingly, at all elevated BMI levels, had decreased insulin receptor-1 (IRS-1) levels, decreased Akt activity, and increased expression/abundance of aPKC-ι and PGC-1α. Moreover, with increasing BMI, there were: progressive increases in aPKC activity and PKC-ι expression/abundance; progressive decreases in IRS-1 levels, Akt activity and FoxO1 phosphorylation; progressive increases in expression/abundance of PGC-1α; and progressive increases in gluconeogenic and lipogenic enzymes. Remarkably, all abnormalities reached T2D levels at higher BMI levels. Most importantly, both “early” and advanced abnormalities were largely reversed by 24-hour treatment of T2D hepatocytes with aPKC inhibitor. We conclude: hepatic insulin resistance in human obesity is: advanced; BMI-correlated; and sequentially involves increased aPKC-activating ceramide; increased aPKC levels and activity; decreases in IRS-1 levels, Akt activity, and FoxO1 phosphorylation; and increases in expression/abundance of PGC-1α and gluconeogenic and lipogenic genes.

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Phosphorylation and Recruitment of BAF60c in Chromatin Remodeling for Lipogenesis in Response to Insulin

Cited by 65 publications

References 40 publications

Transcriptional regulation of hepatic lipogenesis

Transcriptional regulation of hepatic lipogenesis

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

BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans

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