Transcription factor ISX mediates the cross talk between diet and immunity

Widjaja‐Adhi, Made Airanthi K.; Palczewski, Grzegorz; Dale, Kali; Knauss, Elizabeth A.; Kelly, Mary Ellen; Golczak, Marcin; Levine, Alan D.; Lintig, Johannes von

doi:10.1073/pnas.1714963114

Cited by 39 publications

(32 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To probe in vivo the contributions of the two CCDs to the metabolism of an asymmetric provitamin A carotenoid, we employed mice lacking the transcription factor ISX ( Isx −/− mice). These mice display significantly higher intestinal carotenoid absorption and conversion rates than wild type (WT) mice (35). As model carotenoids, we used the symmetric BC and the asymmetric CX.…”

Section: Resultsmentioning

confidence: 99%

The Biochemical Basis of Vitamin A Production from the Asymmetric Carotenoid β-Cryptoxanthin

et al. 2018

Self Cite

View full text Add to dashboard Cite

Vitamin A serves essential functions in mammalian biology as a signaling molecule and chromophore. This lipid can be synthesized from more than 50 putative dietary provitamin A precursor molecules which contain at least one unsubstituted β-ionone ring. We here scrutinized the enzymatic properties and substrate specificities of the two structurally related carotenoid cleavage dioxygenases (CCDs) which catalyze this synthesis. Recombinant BCO1 split substrates across the C15,C15' double bond adjacent to a canonical β-ionone ring site to vitamin A aldehyde. Substitution of the ring with a hydroxyl group prevented this conversion. The removal of methyl groups from the polyene carbon backbone of the substrate did not impede enzyme activity. Homology modeling and site-directed mutagenesis identified amino acid residues at the entrance of the substrate tunnel, which determined BCO1's specificity for the canonical β-ionone ring site. In contrast, BCO2 split substrates across the C9,C10 double bond adjacent to assorted ionone ring sites. Kinetic analysis revealed a higher catalytic efficiency of BCO2 with substrates bearing 3-hydroxy-β-ionone rings. In the mouse intestine, the asymmetric carotenoid β-cryptoxanthin with one canonical and one 3-hydroxy-β-ionone ring site was meticulously converted to vitamin A. The tailoring of this asymmetric substrate occurred by a stepwise processing of the carotenoid substrate by both CCDs and involved a β-apo-10'-carotenal intermediate. Thus, opposite selectivity for ionone ring sites of the two mammalian CCDs complement each other in the metabolic challenge of vitamin A production from a chemically diverse set of precursor molecules.

show abstract

Section: Resultsmentioning

confidence: 99%

The Biochemical Basis of Vitamin A Production from the Asymmetric Carotenoid β-Cryptoxanthin

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…We previously reported that gastrointestinal immunity is severely impaired in ISX-deficient mice when subjected to BC feeding (42). We now observed that the different diets had a profound effect on gastrointestinal immunity and barrier function in LRAT-deficient mice.…”

Section: Discussionmentioning

confidence: 63%

LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene

Ramkumar

Moon

Golczak

et al. 2021

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

There is increasing recognition that dietary lipids can affect the expression of genes encoding their metabolizing enzymes, transporters, and binding proteins. This mechanism plays a pivotal role in controlling tissue homeostasis of these compounds and avoiding diseases. The regulation of retinoid biosynthesis from β-carotene (BC) is a classic example for such an interaction. The intestine-specific homeodomain transcription factor (ISX) controls the activity of the vitamin A-forming enzyme β-carotene oxygenase-1 in intestinal enterocytes in response to increasing concentration of the vitamin A metabolite retinoic acid. However, it is unclear how cells control the concentration of the signaling molecule in this negative-feedback loop. We demonstrate in mice that the sequestration of retinyl esters by the enzyme lecithin:retinol acyltransferase (LRAT) is central for this process. Using genetic and pharmacological approaches in mice, we observed that in LRAT deficiency, the transcription factor ISX became hypersensitive to dietary vitamin A and suppressed retinoid biosynthesis. The dysregulation of the pathway resulted in BC accumulation and vitamin A deficiency of extrahepatic tissues. Pharmacological inhibition of retinoid signaling and genetic depletion of the Isx gene restored retinoid biosynthesis in enterocytes. We provide evidence that the catalytic activity of LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis and maintains optimal retinoid levels in the body.Supplementary key words enterocytes • retinoids • carotenoids • cell signaling • metabolism • lipids • LRAT • vitamin A *For correspondence: Johannes von Lintig, johannes.vonlintig@case.edu.

show abstract

“…Notably, among the all members of the hypoxia-responsive gene set ( ISX, CLCA4 , SLC5A8, TEX11, CRABP1, CLC12 , and BGN1 ), Intestinal Specific homeobox protein (ISX ) is the prominant factor that is reported to be involved in metabolic activities and disorders in humans. ISX has been reported to regulate the metabolic flux and immune system [38]. This generated an interest to study the relevance and function of ISX in PDAC disease.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression

Ganaie

Parray

Hussain

et al. 2019

Translational Oncology

View full text Add to dashboard Cite

Therapy failure and metastasis-associated mortality are stumbling blocks in the management of PDAC in patients. Failure of therapy is associated to intense hypoxic conditions of tumors. To develop effective therapies, a complete understanding of hypoxia-associated changes in genetic landscape of tumors during disease progression is needed. Because artificially immortalized cell lines do not rightly represent the disease progression, studying genetics of tumors in spontaneous models is warranted. In the current study, we generated a spectrum of spontaneous human (UM-PDC1; UM-PDC2) and murine (HI-PanL, HI-PancI, HI-PanM) models representing localized, invasive, and metastatic PDAC from a patient and transgenic mice ( K-ras G12D /Pdx cre /Ink4a/p16 -/ ). These spontaneous models grow vigorously under hypoxia and exhibit activated K-ras signaling, progressive loss of PTEN, and tumorigenicity in vivo. Whereas UM-PDC1 form localized tumors, the UM-PDC2 metastasize to lungs in mice. In an order of progression, these models exhibit genomic instability marked by gross chromosomal rearrangements, centrosome-number variations, Aurora-kinase/H2AX colocalization, loss of primary cilia, and α-tubulin acetylation. The RNA sequencing of hypoxic models followed by qRT-PCR validation and gene-set enrichment identified Intestine-Specific Homeobox factor ( ISX ) – driven molecular pathway as an indicator PDAC aggressivness. TCGA-PAAD clinical data analysis showed high ISX expression correlation to poor survival of PDAC patients, particularly women. The functional studies showed ISX as a regulator of i) invasiveness and migratory potential and ii) VEGF , MMP2 , and NFκB activation in PDAC cells. We suggest that ISX is a potential druggable target and newly developed spontaneous cell models are valuable tools for studying mechanism and testing therapies for PDAC.

show abstract

Transcription factor ISX mediates the cross talk between diet and immunity

Cited by 39 publications

References 38 publications

The Biochemical Basis of Vitamin A Production from the Asymmetric Carotenoid β-Cryptoxanthin

The Biochemical Basis of Vitamin A Production from the Asymmetric Carotenoid β-Cryptoxanthin

LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene

Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression

Contact Info

Product

Resources

About