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  • AKR D is very highly expressed in

    2021-09-14

    AKR1D1 is very highly expressed in human liver and based upon the observations outlined above, with respect to other steroid hormone pre-receptor metabolising enzymes, it is entirely plausible that AKR1D1 could represent a critical regulatory step in the control of metabolic phenotype within the liver. There is an established body of evidence highlighting the role of the GR in the regulation of carbohydrate metabolism; glucocorticoids perform their metabolic role through activation of the GR and regulate the expression of major gluconeogenic enzymes such as PCK1, G6Pase and tyrosine aminotransferase [46]. Furthermore, hepatocyte specific GR knockout mice exhibit hypoglycaemia after prolonged fasting due to impaired gluconeogenic enzyme expression [47]. Glucocorticoids also regulate lipid metabolism in a variety of tissues including adipose tissue and the liver [[48], [49], [50], [51]]. Rodent studies including primary cultures of rat hepatocytes have demonstrated increased activity of hepatic acetyl-CoA carboxylase (rate limiting step of DNL) and fatty Darunavir Ethanolate synthase after glucocorticoid treatment [52] as well as increased lipogenesis after glucocorticoid treatment in the presence of insulin [53]. Consistent with this, cortisol treatment has been reported to increase lipogenesis following insulin stimulation in primary human hepatocytes [51]. Moreover, Darunavir Ethanolate decreased cortisol clearance via 5αR1 deletion has also been associated with hepatic steatosis in mice [9]. Taken together, these observations demonstrate not only the potent ability of glucocorticoids to manipulate metabolic phenotype in the liver, but also the critical role that pre-receptor regulation can play. Specifically, with regards to AKR1D1, there are currently no published data on genetically modified animal models that might help aid our understanding of the true role of AKR1D1 in vivo and there are very limited clinical data. A single paper has suggested that there is decreased expression in liver biopsies from patients with diabetes when compared against non-diabetic controls [54]. An additional study that examined AKR1D1 activity using urinary steroid metabolites suggested that increased activity was associated with increased hepatic lipid content [55]. The ability of AKR1D1 to regulate cytosolic availability of a variety of steroid hormones in human hepatocytes indicates the presence of an intracellular complex system for steroid hormone metabolism. However, in addition, AKR1D1 performs a fundamental step in BA synthesis, as it is involved in an intermediate step in both the classic and alternative BA synthesis pathway, that lead to the generation of the primary BAs cholic acid and chenodeoxycholic acid. BAs are now well established as important signalling molecules, acting locally as well as in distant tissues, and are key regulators of systemic metabolism [56], and therefore the role that AKR1D1 plays in BA synthesis adds a further layer of complexity to the mechanisms that may underpin the role of this enzyme to regulate metabolic phenotype. Although the important role of AKR1D1 in steroid hormone metabolism is now evident, to date, no specific pharmacological inhibitors for AKR1D1 are available. A previous study by Drury et al. 2009 reported that finasteride, a specific 5αR type 2 inhibitor, partially inhibited AKR1D1 activity [23]. Our cell-based studies have now provided evidence to suggest that finasteride is able to impact a modest inhibitory action on AKR1D1 (but much less so with the non-selective inhibitor, dutasteride). However, considering that cortisone can also be metabolized by 5αRs [57,58], it is possible the inhibition of cortisone clearance that we observed could have been mediated (at least in part), by the ability of finasteride to inhibit 5αR activity. The development of potent and specific inhibitors of AKR1D1 activity will undoubtedly enhance our ability to dissect the role of AKR1D1 cellular function and may also have therapeutic potential in metabolic disease, but this remains to be formally evaluated.