Endocrine Abstracts

Objective:

The activity of hepatic enzymes that metabolise glucocorticoids is altered in the setting of the metabolic syndrome. Westerbacka et al suggested a specific association between fatty liver and increased 5beta-reductase enzyme activity (J Clin Endocrinol Metab 2003). We hypothesised that non-alcoholic fatty liver disease (NAFLD), which is strongly associated with insulin resistance, may be primarily responsible for these changes.

Design:

A non-insulin resistant non-obese model of NAFLD, the choline-deficient diet (CDD) in mice, was used to examine changes in glucocorticoid enzyme expression and metabolism.

Methods:

Mice were fed a CDD or control diet for 3 weeks, after which the levels of mRNA and activity of hepatic 11 beta- hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), the enzyme that reactivates inert products (cortisone in man, and 11-dehydrocorticosterone in rodents) to the active glucocorticoid cortisol (corticosterone in rodents), and the A-ring reductases 5 alpha- and 5 beta-reductase, which control the rate limiting steps of glucocorticoid breakdown, were measured.

Results:

The CDD induced fatty livers (liver triglyceride 73.0 plus/minus 16 micromols per gram vs 24.6 plus/minus 7 micromols per gram for the control diet; p = 0.02), but there were no differences between mice on a CDD or control diet in terms of weight gain, insulin and glucose levels or corticosterone levels. The CDD had no significant effect on hepatic expression or activity of GC metabolising enzymes, particularly of 5 beta-reductase (5 beta-reductase mRNA levels 0.44 ± 0.15 vs. 0.37 ± 0.04, p = 0.4; 5 beta-reductase activity = 15.5 ± 2.6 vs. 13.6 ± 4.2, p = 0.4).

Conclusions:

Fatty liver disease in the absence of insulin resistance or obesity does not lead to alterations in the hepatic glucocorticoid metabolising enzymes. We suggest that primary fat accumulation is not the underlying cause of the changes described in the activity of 11 beta-HSD1 or the A-ring reductases in the liver in the metabolic syndrome.