Abstract
This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate (-25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; -29%). ACOL increased liver TG concentration (+100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels (r = 0.80, P < 0.002). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance.
Highlights
This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL)
This study was undertaken to establish the mechanisms by which the SERM ACOL decreases plasma lipids
It was found that triglyceridemia was decreased by ACOL under the present dietary conditions, mainly as a result of a reduced rate of VLDL-TG secretion, which in turn was associated with a decrease in microsomal triglyceride transfer protein (MTP) mRNA levels
Summary
This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). In the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels (r ؍0.80, P Ͻ 0.002). Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors. Despite its pure antiestrogenic activity in the mammary gland and endometrium, ACOL can be classified as a SERM based on some estrogen-like properties, such as prevention of bone loss, decreasing plasma lipids [7,8,9], and reduction in body weight (mostly fat) gain [9, 10] in animal models. Because ACOL is a SERM, it appeared of primary interest to determine whether or not the drug exerts estrogen-like actions on these liver receptors as well as on key determinants of hepatic CHOL synthesis and metabolism
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