Repression of glucocorticoid-stimulated angiopoietin-like 4 gene transcription by insulin

Kuo, Taiyi; Chen, Tzu-Chieh; Yan, Stephanie; Foo, Fritz; Ching, Cecilia; McQueen, Allison; Wang, Jen-Chywan

doi:10.1194/jlr.m047860

Cited by 32 publications

(23 citation statements)

References 57 publications

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“…RNA Isolation, Quantitative PCR, and RNA Sequencing. We isolated total RNA Nucleospin RNA kit (Macherey-Nagel), and followed previously described protocol for reverse transcription (64). The detailed protocol and primer sequences are presented in SI Appendix, SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Identification of C2CD4A as a human diabetes susceptibility gene with a role in β cell insulin secretion

Kuo

Kraakman

Damle

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Fine mapping and validation of genes causing β cell failure from susceptibility loci identified in type 2 diabetes genome-wide association studies (GWAS) poses a significant challenge. The VPS13C-C2CD4A-C2CD4B locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1 is involved in the pathogenesis of β cell dysfunction, but its link to human diabetes GWAS has not been explored. Here we generated a genome-wide map of FoxO1 superenhancers in chemically identified β cells using 2-photon live-cell imaging to monitor FoxO1 localization. When parsed against human superenhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved superenhancer in C2CD4A, a gene encoding a β cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in β cells of mice phenocopied the metabolic abnormalities of human carriers of C2CD4A-linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2CD4A regulates glycolytic genes, and notably represses key β cell “disallowed” genes, such as lactate dehydrogenase A. We propose that C2CD4A is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.

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Section: Methodsmentioning

confidence: 99%

Identification of C2CD4A as a human diabetes susceptibility gene with a role in β cell insulin secretion

Kuo

Kraakman

Damle

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…RNA isolation and quantitative PCR. We isolated total RNA from mouse pancreatic islets or β cells sorted with FACS using Nucleospin RNA kit (Macherey-Nagel) and followed previously described protocol for reverse transcription (54). We used the resulting cDNA to perform quantitative PCR with GoTaq master mix (Promega) and analyzed data with the standard ΔΔCt method.…”

Section: Methodsmentioning

confidence: 99%

Induction of α cell–restricted Gc in dedifferentiating β cells contributes to stress-induced β cell dysfunction

Kuo¹,

Damle²,

González³

et al. 2019

JCI Insight

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“…6) and completes the mechanisms proposed by Dijk & Kersten (Dijk & Kersten 2014) concerning the relevance of an ANGPTL-4/LPL axis aimed at clearing TGs from both chylomicrons and VLDL proteins. In regard to the mechanism involved in CCK-8-mediated repression of Angptl-4 expression and decrease of plasma ANGPTL-4 levels, a plausible possibility would involve the PI3K/Akt pathway as this signalling pathway, which has been shown to be pivotal for insulin-mediated repression of the Angptl-4 gene (Kuo et al 2014), is activated by CCK-2R (Dufresne et al 2006). In any case, the versatility of downstream signaling pathways coupled to CCK-2R (Dufresne et al 2006) allows one to hypothesize the involvement of other signaling pathways, such as PPAR-γ (Burns & Heuvel 2007), that is also known to govern Angptl-4 expression.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

Cholecystokinin is involved in triglyceride fatty acid uptake by rat adipose tissue

Plaza

Merino

Cano

et al. 2018

Journal of Endocrinology

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The incorporation of plasma triglyceride (TG) fatty acids to white adipose tissue (WAT) depends on lipoprotein lipase (LPL), which is regulated by angiopoietin-like protein-4 (ANGPTL-4), an unfolding molecular chaperone that converts active LPL dimers into inactive monomers. The production of ANGPTL-4 is promoted by fasting and repressed by feeding. We hypothesized that the postprandial hormone cholecystokinin (CCK) facilitates the storage of dietary TG fatty acids in WAT by regulating the activity of the LPL/ANGPTL-4 axis and that it does so by acting directly on CCK receptors in adipocytes. We report that administration of CCK-8 (a bioactive fragment of CCK) to rats: (i) reduces plasma ANGTPL-4 levels; (ii) represses expression in WAT and (iii) simultaneously enhances LPL activity in this tissue without inducing expression. CCK-8 effects are specifically antagonized by the CCK-2 receptor (CCK-2R) antagonist, L-365,260. Moreover, CCK-8 downregulates expression in wild-type pre-adipocytes, an effect that is not observed in engineered pre-adipocytes lacking CCK-2R. These effects have functional consequences as CCK-8 was found to promote the uptake of dietary fatty acids by WAT, as demonstrated by means of proton nuclear magnetic resonance (H-NMR). The efficacy of acute CCK-8 administration was not reduced after chronic CCK-8 treatment. Moreover, the effects of CCK-8 on WAT were not associated to the increase of circulating insulin. Our results show that cholecystokinin promotes lipid storage in WAT by acting on adipocyte CCK-2R, suggesting a pivotal role for CCK in TG homeostasis.

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Repression of glucocorticoid-stimulated angiopoietin-like 4 gene transcription by insulin

Cited by 32 publications

References 57 publications

Identification of C2CD4A as a human diabetes susceptibility gene with a role in β cell insulin secretion

Identification of C2CD4A as a human diabetes susceptibility gene with a role in β cell insulin secretion

Induction of α cell–restricted Gc in dedifferentiating β cells contributes to stress-induced β cell dysfunction

Cholecystokinin is involved in triglyceride fatty acid uptake by rat adipose tissue

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