Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation

Chem Biol Interact. 2011 May 30;191(1-3):278-87. doi: 10.1016/j.cbi.2011.01.013. Epub 2011 Jan 20.


Reactive lipid aldehydes are implicated in the pathogenesis of various oxidative stress-mediated diseases, including non-alcoholic steatohepatitis, atherosclerosis, Alzheimer's and cataract. In the present study, we sought to define which hepatic Aldh isoform plays a major role in detoxification of lipid-derived aldehydes, such as acrolein and HNE by enzyme kinetic and gene expression studies. The catalytic efficiencies for metabolism of acrolein by Aldh1a1 was comparable to that of Aldh3a1 (V(max)/K(m)=23). However, Aldh1a1 exhibits far higher affinity for acrolein (K(m)=23.2 μM) compared to Aldh3a1 (K(m)=464 μM). Aldh1a1 displays a 3-fold higher catalytic efficiency for HNE than Aldh3a1 (218 ml/min/mg vs 69 ml/min/mg). The endogenous Aldh1a1 gene was highly expressed in mouse liver and a liver-derived cell line (Hepa-1c1c7) compared to Aldh2, Aldh1b1 and Aldh3a1. Aldh1a1 mRNA levels was 34-fold and 73-fold higher than Aldh2 in mouse liver and Hepa-1c1c7 cells respectively. Aldh3a1 gene was absent in mouse liver, but moderately expressed in Hepa-1c1c7 cells compared to Aldh1a1. We demonstrated that knockdown of Aldh1a1 expression by siRNA caused Hepa-1c1c7 cells to be more sensitive to acrolein-induced cell death and resulted in increased accumulation of acrolein-protein adducts and caspase 3 activation. These results indicate that Aldh1a1 plays a major role in cellular defense against oxidative damage induced by reactive lipid aldehydes in mouse liver. We also noted that hepatic Aldh1a1 mRNA levels were significantly increased (≈3-fold) in acrolein-fed mice compared to control. In addition, hepatic cytosolic ALDH activity was induced by acrolein when 1mM NAD(+) was used as cofactor, suggesting an Aldh1a1-protective mechanism against acrolein toxicity in mice liver. Thus, mechanisms to induce Aldh1a1 gene expression may provide a useful rationale for therapeutic protection against oxidative stress-induced pathologies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acrolein / pharmacology
  • Aldehyde Dehydrogenase / deficiency
  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase 1 Family
  • Aldehydes / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Kinetics
  • Lipid Peroxidation* / drug effects
  • Lipid Peroxidation* / genetics
  • Liver / enzymology*
  • Mice
  • Retinal Dehydrogenase
  • Substrate Specificity


  • Aldehydes
  • Acrolein
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • Aldh3a1protein, mouse
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • Caspase 3