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Literature summary for 1.1.1.21 extracted from

  • Thiagarajan, D.; Ananthakrishnan, R.; Zhang, J.; OShea, K.M.; Quadri, N.; Li, Q.; Sas, K.; Jing, X.; Rosario, R.; Pennathur, S.; Schmidt, A.M.; Ramasamy, R.
    Aldose reductase acts as a selective derepressor of PPARgamma and the retinoic acid receptor (2016), Cell Rep., 15, 181-196.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
gene AKR1B1, recombinant cardiomyocyte-specific overexpression of human enzyme in transgenic mice, adenoviral transduction. Expression in mice hearts leads to a decrease in histone deacetylase 3, HDAC3, levels accompanied by an increase in PPARgamma activity thereby contributing to lipid-enriched environment, enzyme expression leads to lipid accumulation. Human enzyme expression leads to reduced histone deacetylase 3 corepressor complexes with consequent increases in RARB in the nucleus and derepression of its target gene expression Homo sapiens

Protein Variants

Protein Variants Comment Organism
additional information construction of enzyme knockout, ARKO, mice and of mice overexpressing the human enzyme in a cardiospecific manner, i.e. MHC-hAR mice. Increased PPARgamma and reduced CEBPalpa expression occur in the nuclear fractions of MHC-hAR hearts compared to wild-type and ARKO, indicating increased PPARgamma to be the driving force for increased lipid accumulation by human recombinant enzyme Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytoplasm
-
Homo sapiens 5737
-
nucleus
-
Homo sapiens 5634
-

Organism

Organism UniProt Comment Textmining
Homo sapiens P15121
-
-

Source Tissue

Source Tissue Comment Organism Textmining
blood plasma
-
Homo sapiens
-
cardiomyocyte
-
Homo sapiens
-
H9c2 cell
-
Homo sapiens
-
HAEC cell
-
Homo sapiens
-
heart
-
Homo sapiens
-
HUVEC cell
-
Homo sapiens
-

Synonyms

Synonyms Comment Organism
AKR1B1 gene name, UniProt Homo sapiens
aldose reductase
-
Homo sapiens

General Information

General Information Comment Organism
malfunction left ascending coronary artery ligation followed by 48 hrs of reperfusion is used as an ischemia-reperfusion (I/R) model, show a twofold increase in serum and myocardial triglycerides in cardiomyocyte-specific human AR (MHC-hAR) expressing mice compared to wild-type, whereas in global enzyme AR knockout mice, triglyceride levels are lower or comparable to wild-type subjected to I/R. Under basal conditions (in the absence of I/R), no changes triglyceride, but 2fold increased free fatty acids and a 2.5fold increase in PPARgamma expresssion occur in serum of MHC-hAR mice versus wild-type and the levels are comparable in wild-type and knockout mice, phenotypes, overview Homo sapiens
metabolism first and rate-limiting step of the polyol pathway. Distinct role for aldose reductase in lipid and retinoid metabolism through histone deacetylase 3 regulation and consequent derepression of PPARgamma and the retinoic acid receptor Homo sapiens
physiological function aldose reductase plays a critical role in mediating cardiovascular complications in diabetes, aging, and ischemia-reperfusion injury. Aldose reductase acts as a selective derepressor of PPARgamma and the retinoic acid receptor. Increased enzyme expression leads to histone deacetylase 3 degradation followed by increased PPARgamma signaling resulting in lipid accumulation in the heart. The enzyme also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, affecting activity of the nuclear corepressor complex itself. Though aldose reductase reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor, but not other nuclear receptors such as the thyroid receptor and liver X receptor. Mechanisms by which hAR drives lipid accumulation in the heart, overview. The human enzyme competes with histone deacetylase 3 for the deacetylase containing domain, DAD, the nuclear receptor co-repressors NCOR1 and SMRT. Residue L289 of the human enzyme is essential for DAD interaction. DAD supplementation rescues the reduction in HDAC3 activity in the presence of recombinant aldose reductase Homo sapiens