The role of bile acids in the therapy of selected diseases / Znaczenie kwasów zólciowych w terapii wybranych chorób.

The main function of bile acids (BA) is participation in the emulsification of dietary fats. Recently it has been discovered that BAs can also act as signaling molecules regulating the processes of their own synthesis and metabolism, as well as glucose and lipid metabolism. In addition, they affect the motility of the digestive tract and food intake. BA also interacts with the gut microbiota, a major player in their metabolism. Most of the regulatory actions of BAs are mediated by their receptors, the most important of which are the farnesoid X receptor (FXR) and the G protein-coupled receptor -TGR5, found in large amounts in the intestine, liver, adipose tissue and other tissues of the body. Recently, much attention has been paid to the influence of BA on various diseases and the possibility of using them in the treatment of e.g. inflammatory bowel disease, liver diseases, type 2 diabetes and obesity.

Hydroxysteroid 17-ß dehydrogenase 14 (HSD17B14) is an L-fucose dehydrogenase, the initial enzyme of the L-fucose degradation pathway.

L-Fucose (6-deoxy-L-galactose), a monosaccharide abundant in glycolipids and glycoproteins produced by mammalian cells, has been extensively studied for its role in intracellular biosynthesis and recycling of GDP-L-fucose for fucosylation. However, in certain mammalian species, L-fucose is efficiently broken down to pyruvate and lactate in a poorly understood metabolic pathway. In the 1970s, L-fucose dehydrogenase, an enzyme responsible for the initial step of this pathway, was partially purified from pig and rabbit livers and characterized biochemically. However, its molecular identity remained elusive until recently. This study reports the purification, identification, and biochemical characterization of the mammalian L-fucose dehydrogenase. The enzyme was purified from rabbit liver approximately 340-fold. Mass spectrometry analysis of the purified protein preparation identified mammalian hydroxysteroid 17-ß dehydrogenase 14 (HSD17B14) as the sole candidate enzyme. Rabbit and human HSD17B14 were expressed in HEK293T and Escherichia coli, respectively, purified, and demonstrated to catalyze the oxidation of L-fucose to L-fucono-1,5-lactone, as confirmed by mass spectrometry and NMR analysis. Substrate specificity studies revealed that L-fucose is the preferred substrate for both enzymes. The human enzyme exhibited a catalytic efficiency for L-fucose that was 359-fold higher than its efficiency for estradiol. Additionally, recombinant rat HSD17B14 exhibited negligible activity towards L-fucose, consistent with the absence of L-fucose metabolism in this species. The identification of the gene-encoding mammalian L-fucose dehydrogenase provides novel insights into the substrate specificity of enzymes belonging to the 17-ß-hydroxysteroid dehydrogenase family. This discovery also paves the way for unraveling the physiological functions of the L-fucose degradation pathway, which remains enigmatic.