Tamoxifen reduces hepatic VLDL production and GH secretion in women: a possible mechanism for steatosis development
CONTEXT: Growth hormone (GH) stimulates hepatic synthesis of very-low-density lipoproteins (VLDL), whereas hepatic steatosis develops as a result of GH deficiency. Steatosis is also a complication of tamoxifen treatment, the cause of which is not known. As tamoxifen inhibits the secretion and action of GH, we hypothesize that it induces steatosis by inhibiting hepatic VLDL export. AIM: To investigate whether tamoxifen reduces hepatic VLDL secretion. DESIGN: Eight healthy, normolipidemic women (age: 64.4 +/- 2.1 years) were studied in random sequence at baseline, after 2 weeks of tamoxifen (20 mg/day) and after 2 weeks of estradiol valerate (EV; 2 mg/day) treatments, separated by a 4-week washout period. The kinetics of apolipoprotein B (apoB), the structural protein of VLDL particles, were measured using a stable isotope 2H(3)-leucine turnover technique. VLDL-apoB fractional catabolic rate (FCR) was determined using a multicompartment model. VLDL-apoB secretion was estimated as the product of FCR and VLDL-apoB concentration. GH response to arginine stimulation, circulating levels of IGF-1, FFA, and TG, along with TG content in VLDL were measured. RESULTS: Tamoxifen significantly (P < 0.05) reduced VLDL-apoB concentration and secretion by 27.3 +/- 7.8% and 29.8 +/- 10.2%, respectively. In contrast, EV did not significantly change VLDL-apoB concentration or secretion. Tamoxifen but not EV significantly reduced (P < 0.05) GH response to arginine stimulation. Both treatments significantly lowered (P < 0.05) circulating IGF-1. CONCLUSION: Inhibition of VLDL secretion may contribute to the development of fatty liver during tamoxifen therapy. As GH stimulates VLDL secretion, the development of steatosis may arise secondarily from GH insufficiency induced by tamoxifen.
|ISBN||1479-683X (Electronic) 0804-4643 (Linking)|
|Authors||Birzniece, V.; Barrett, P. H. R.; Ho, K. K. Y.|
|Responsible Garvan Author|
|Publisher Name||EUROPEAN JOURNAL OF ENDOCRINOLOGY|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/28500244|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14422|