Aldose reductase, fructose and fat production in the liver

There is an increasing interest in the role of fructose as a major driver of non-alcoholic fatty liver disease (NAFLD), and it is linked closely with the intake of sugar. However, there has also been the recognition that fructose can be produced directly from intracellular glucose via the evolutionarily conserved polyol pathway whose access is governed by aldose reductase (AR). The purpose of this article is to review the biochemistry of AR and the role of the polyol pathway in opening fructose metabolism. This article provides a new perspective about AR and the other key enzymes surrounding the decision to divert glucose into the polyol pathway which suggests that the production of endogenous fructose may be of much greater significance than historically viewed. There are important aspects of the regulation of the polyol pathway and its committal step catalyzed by AR, which supports the notion that fructose-uric acid pathway is activated by elevated glucose with the downstream consequence of NAFLD and perhaps other chronic metabolic diseases.