Reductive detoxification of acrolein as a potential role for aldehyde reductase (AKR1A) in mammals.

Aldehyde reductase (AKR1A), a member of the aldo-keto reductase superfamily, suppresses diabetic complications via a reduction in metabolic intermediates; it also plays a role in ascorbic acid biosynthesis in mice. Because primates cannot synthesize ascorbic acid, a principle role of AKR1A appears to be the reductive detoxification of aldehydes. In this study, we isolated and immortalized mouse embryonic fibroblasts (MEFs) from wild-type (WT) and human Akr1a-transgenic (Tg) mice and used them to investigate the potential roles of AKR1A under culture conditions. Tg MEFs showed higher methylglyoxal- and acrolein-reducing activities than WT MEFs and also were more resistant to cytotoxicity. Enzymatic analyses of purified rat AKR1A showed that the efficiency of the acrolein reduction was about 20% that of glyceraldehyde. Ascorbic acid levels were quite low in the MEFs, and while the administration of ascorbic acid to the cells increased the intracellular levels of ascorbic acid, it had no affect on the resistance to acrolein. Endoplasmic reticulum stress and protein carbonylation induced by acrolein treatment were less evident in Tg MEFs than in WT MEFs. These data collectively indicate that one of the principle roles of AKR1A in primates is the reductive detoxification of aldehydes, notably acrolein, and protection from its detrimental effects.

A malfunction in triglyceride transfer from the intracellular lipid pool to apoB in enterocytes of SOD1-deficient mice.

We compared lipid metabolism in the intestines of Sod1-knockout mice with that found in wild-type mice to elucidate the impact of oxidative stress in vivo. A high-fat diet in wild-type mice induced postprandial hypertriglyceridemia, but this adaptive response was impaired in Sod1-knockout mice. While fewer triglycerides were secreted to the blood in the form of triglyceride-rich lipoprotein, more lipid droplets accumulated in the enterocytes of Sod1-knockout mice fed a high-fat diet. These data collectively suggest that high-fat diet induces oxidative stress, inhibits lipid secretion to the blood, and ultimately leads to dysfunctional lipid metabolism in enterocytes.