Docent Magnus Axelson
Magnus Axelson, bitr. öl, docent<maax@cc.ks.se>
tel 729 3528 fax 31 03 76
Per Fahlstadius, ST-läkare, dr med vet

Research project: Steroid metabolism in health and disease

General and selective methods for analysis of steroids in biological materials, based on liquid-gel chromatography, high-performance liquid chromatography and gas chromatography-mass spectrometry, are being developed. The methods are used for studies of:

    1. Biosynthesis of cholesterol and formation of bile acids in the liver.
    2. Regulation of cholesterol homeostasis in human cells.
    3. Metabolism of sulphated vitamin D3 in humans.
    4. Metabolism of phytoestrogens present in the diet.
    5. Metabolic profiles of steroid hormones in tissues and body fluids.

Research results:

A comprehensive screening of the biological activity of essentially all intermediates in the biosynthesis of bile acids has been made. For this purpose 23 intermediates were synthesized and their effects on HMG-CoA reductase (the rate-limiting enzyme in cholesterol biosynthesis) in cultured human fibroblasts were tested. A new group of potent inhibitors of the enzyme was discovered. These inhibitors all had a 3-oxo-D4 structure, which is characteristic of potent steroid hormones.

The results also show that only a few specific intermediates in the formation of bile acids are potent suppressors of HMG-CoA reductase. Alternative pathways to bile acids may therefore have different regulatory roles in cholesterol biosynthesis, depending on the biological activities of the intermediates involved.

Previously I have shown that 7-dehydrocholesterol (7-DHC) occurs in human plasma and the results indicated that its level may reflect the production of cholesterol. Plasma levels of 7-DHC have now been compared with activities of HMG-CoA reductase assayed in liver biopsies from patients undergoing cholecystectomy. The results show that there was a strong positive correlation between the plasma levels of the sterol and the activities of the enzyme suggesting that analysis of 7-DHC in plasma can be a convenient method to determine relative rates of cholesterol production in humans.

Selected references:

M. Axelson, O. Larsson, J. Zhang, J. Shoda, J. Sjövall: Structural specificity in the inhibition of HMG-CoA reductase in human fibroblasts by intermediates in bile acid biosynthesis. J. Lipid Research, 36, 290-298, 1995.

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