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 | 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 | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
cytoplasm | - |
Homo sapiens | 5737 | - |
nucleus | - |
Homo sapiens | 5634 | - |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P15121 | - |
- |
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 | Comment | Organism |
---|---|---|
AKR1B1 | gene name, UniProt | Homo sapiens |
aldose reductase | - |
Homo sapiens |
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 |