Aldo-Keto Reductases 1B in Endocrinology and Metabolism

Abstract

The aldose reductase (AR; human AKR1B1/mouse Akr1b3) has been the focus of many research because of its role in diabetic complications. The starting point of these alterations is the massive entry of glucose in polyol pathway where it is converted into sorbitol by this enzyme. However, the issue of AR function in non-diabetic condition remains unresolved. AR-like enzymes (AKR1B10, Akr1b7, and Akr1b8) are highly related isoforms often co-expressed with bona fide AR, making functional analysis of one or the other isoform a challenging task. AKR1B/Akr1b members share at least 65% protein identity and the general ability to reduce many redundant substrates such as aldehydes provided from lipid peroxidation, steroids and their by-products, and xenobiotics in vitro. Based on these properties, AKR1B/Akr1b are generally considered as detoxifying enzymes. Considering that divergences should be more informative than similarities to help understanding their physiological functions, we chose to review specific hallmarks of each human/mouse isoforms by focusing on tissue distribution and specific mechanisms of gene regulation. Indeed, although the AR shows ubiquitous expression, AR-like proteins exhibit tissue-specific patterns of expression. We focused on three organs where certain isoforms are enriched, the adrenal gland, enterohepatic, and adipose tissues and tried to connect recent enzymatic and regulation data with endocrine and metabolic functions of these organs. We presented recent mouse models showing unsuspected physiological functions in the regulation of glucido-lipidic metabolism and adipose tissue homeostasis. Beyond the widely accepted idea that AKR1B/Akr1b are detoxification enzymes, these recent reports provide growing evidences that they are able to modify or generate signal molecules. This conceptually shifts this class of enzymes from unenviable status of scavenger to upper class of messengers.

Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls

“…It was detected in testis, heart, adrenal glands, intestine and liver [80] and was subsequently shown to be capable of reducing several different substrates [81]. Mouse AKR1B8 associates with murine acetyl-CoA carboxylase-α and mediates fatty acid synthesis in colon cancer cells [82].…”

“…Mouse AKR1B8 associates with murine acetyl-CoA carboxylase-α and mediates fatty acid synthesis in colon cancer cells [82]. In vitro , the purified enzyme is capable of catalyzing the reduction of both free and phospholipid bound aldehydes [66], therefore AKR1B8 could act as a physiological scavenger of toxic RCS (Table 1) derived from lipid-peroxidation in several tissues where it is expressed [80]. Because its expression is induced by growth factors, the enzyme may be one potential mechanism, by which growth factors enhance resistance to oxidative injury and cell death.…”

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

“…This may explain the large quantity of endogenous anti-oxidant compounds (vitamin E, β-carotene, and vitamin C) (Hornsby & Crivello 1983) and the presence of enzymes implicated in detoxification of steroidogenesis by-products (Martinez et al 2001) in the adrenal glands (Lefrançois- Martinez et al 1999, Chinn et al 2002. To prevent cell toxicity, these reactive oxygen species (ROS) are metabolized to isocaproic acid by a family of aldo-keto reductases (AKR), including Akr1b8 and Akr1b7 in mice and AKR1B10 in humans (Lefrançois- Martinez et al 1999, Pastel et al 2012. These enzymes are highly expressed in the adrenal glands, and their levels of expression are correlated with the level of ACTH (Schimmer et al 2007).…”

Global gene expression profiling using heterologous DNA microarrays to analyze alterations in the transcriptome of Mus spretus mice living in a heavily polluted environment

“…AKR1C18 has retinaldehyde reductase activity, depleting the substrate of RA biosynthesis ). The Akr1c18 gene was downregulated (∼4-fold) in DRS mice, which may prevent the protection of cells against lipid peroxidation, but helps ADH to enhance the RA signaling pathway and avoid cell proliferation and tumorigenesis (Pastel et al 2012). …”