Dataset Information

Impaired Barrier Function and Immunity in the Colon of Aldo-Keto Reductase 1B8 Deficient Mice.

ABSTRACT: Aldo-keto reductase 1B10 (AKR1B10) is downregulated in human ulcerative colitis (UC) and colorectal cancer, being a potential pathogenic factor of these diseases. Aldo-keto reductase 1B8 (AKR1B8) is the ortholog in mice of human AKR1B10. Targeted AKR1B8 deficiency disrupts homeostasis of epithelial self-renewal and leads to susceptibility to colitis and carcinogenesis. In this study, we found that in AKR1B8 deficient mice, Muc2 expression in colon was diminished, and permeability of colonic epithelium increased. Within 24 h, orally administered FITC-dextran penetrated into mesenteric lymph nodes (MLN) and liver in AKR1B8 deficient mice, but not in wild type controls. In the colon of AKR1B8 deficient mice, neutrophils and mast cells were markedly infiltrated, ??T cells were numerically and functionally impaired, and dendritic cell development was altered. Furthermore, Th1, Th2, and Th17 cells decreased, but Treg and CD8T cells increased in the colon and MLN of AKR1B8 deficient mice. In colonic epithelial cells of AKR1B8 deficient mice, p-AKT (T308 and S473), p-ERK1/2, p-IKB?, p-p65 (S536), and IKK? expression decreased, accompanied with downregulation of IL18 and CCL20 and upregulation of IL1? and CCL8. These data suggest AKR1B8 deficiency leads to abnormalities of intestinal epithelial barrier and immunity in colon.

SUBMITTER: Wang X

PROVIDER: S-EPMC7907435 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Impaired Barrier Function and Immunity in the Colon of Aldo-Keto Reductase 1B8 Deficient Mice.

Wang Xin X Khoshaba Ramina R Shen Yi Y Cao Yu Y Lin Minglin M Zhu Yun Y Cao Zhe Z Liao Duan-Fang DF Cao Deliang D

Frontiers in cell and developmental biology 20210212

Aldo-keto reductase 1B10 (AKR1B10) is downregulated in human ulcerative colitis (UC) and colorectal cancer, being a potential pathogenic factor of these diseases. Aldo-keto reductase 1B8 (AKR1B8) is the ortholog in mice of human AKR1B10. Targeted AKR1B8 deficiency disrupts homeostasis of epithelial self-renewal and leads to susceptibility to colitis and carcinogenesis. In this study, we found that in AKR1B8 deficient mice, Muc2 expression in colon was diminished, and permeability of colonic epit ...[more]

PMID: 33644071

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Project description:Aldo-keto reductases (AKRs) are phase I metabolising enzymes that catalyse the reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H)-dependent reduction of carbonyl groups to yield primary and secondary alcohols on a wide range of substrates, including aliphatic and aromatic aldehydes and ketones, ketoprostaglandins, ketosteroids and xenobiotics. In so doing they functionalise the carbonyl group for conjugation (phase II enzyme reactions). Although functionally diverse, AKRs form a protein superfamily based on their high sequence identity and common protein fold, the (alpha/beta) 8 -barrel structure. Well over 150 AKR enzymes, from diverse organisms, have been annotated so far and given systematic names according to a nomenclature that is based on multiple protein sequence alignment and degree of identity. Annotation of non-vertebrate AKRs at the National Center for Biotechnology Information or Vertebrate Genome Annotation (vega) database does not often include the systematic nomenclature name, so the most comprehensive overview of all annotated AKRs is found on the AKR website (http://www.med.upenn.edu/akr/). This site also hosts links to more detailed and specialised information (eg on crystal structures, gene expression and single nucleotide polymorphisms [SNPs]). The protein-based AKR nomenclature allows unambiguous identification of a given enzyme but does not reflect the wealth of genomic and transcriptomic variation that exists in the various databases. In this context, identification of putative new AKRs and their distinction from pseudogenes are challenging. This review provides a short summary of the characteristic features of AKR biochemistry and structure that have been reviewed in great detail elsewhere, and focuses mainly on nomenclature and database entries of human AKRs that so far have not been subject to systematic annotation. Recent developments in the annotation of SNP and transcript variance in AKRs are also summarised.

Project description:The aldo-keto reductases metabolize a wide range of substrates and are potential drug targets. This protein superfamily includes aldose reductases, aldehyde reductases, hydroxysteroid dehydrogenases and dihydrodiol dehydrogenases. By combining multiple sequence alignments with known three-dimensional structures and the results of site-directed mutagenesis studies, we have developed a structure/function analysis of this superfamily. Our studies suggest that the (alpha/beta)8-barrel fold provides a common scaffold for an NAD(P)(H)-dependent catalytic activity, with substrate specificity determined by variation of loops on the C-terminal side of the barrel. All the aldo-keto reductases are dependent on nicotinamide cofactors for catalysis and retain a similar cofactor binding site, even among proteins with less than 30% amino acid sequence identity. Likewise, the aldo-keto reductase active site is highly conserved. However, our alignments indicate that variation ofa single residue in the active site may alter the reaction mechanism from carbonyl oxidoreduction to carbon-carbon double-bond reduction, as in the 3-oxo-5beta-steroid 4-dehydrogenases (Delta4-3-ketosteroid 5beta-reductases) of the superfamily. Comparison of the proposed substrate binding pocket suggests residues 54 and 118, near the active site, as possible discriminators between sugar and steroid substrates. In addition, sequence alignment and subsequent homology modelling of mouse liver 17beta-hydroxysteroid dehydrogenase and rat ovary 20alpha-hydroxysteroid dehydrogenase indicate that three loops on the C-terminal side of the barrel play potential roles in determining the positional and stereo-specificity of the hydroxysteroid dehydrogenases. Finally, we propose that the aldo-keto reductase superfamily may represent an example of divergent evolution from an ancestral multifunctional oxidoreductase and an example of convergent evolution to the same active-site constellation as the short-chain dehydrogenase/reductase superfamily.

Dataset Information

Impaired Barrier Function and Immunity in the Colon of Aldo-Keto Reductase 1B8 Deficient Mice.

Publications

Impaired Barrier Function and Immunity in the Colon of Aldo-Keto Reductase 1B8 Deficient Mice.

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