Steroid Hormone–Fatty Acid Esters and Bone (2008)

The recent paper by Brodeur et al.1 on the metabolism of low- (LDL) and high-density lipoproteins (HDL) by osteoblastic cells showed for the first time that these cells express scavenger receptors of class B (SR-B). This important study presented a novel mechanism, which explains how cholesterol and estradiol carried by LDL and HDL3 can enter the osteoblast. The authors refer to the previously reported correlation between atherosclerosis and the development of osteoporosis, as well as the well-defined importance of estrogen in bone metabolism. The results of their study suggested that lipoproteins have a significant role in the routing of cholesterol and estradiol to bone cells, to be taken up selectively by a SR-B–mediated process. Interestingly, Gong et al.2 showed SR-B type I–dependent uptake of HDL-associated estradiol into vascular endothelial cells, which implies the possibility of a similar mechanism in these cell types. According to our newly published data, HDL-associated, esterified estradiol is also taken up by liver-derived cells by both SR-B type I and LDL receptors (LDLRs) and becomes hydrolyzed in the cells to free estradiol.3 As Brodeur et al. mention in their paper, estradiol is known to associate with LDL and HDL in fatty acid ester form, a mechanism shared with also other steroid hormones.4, 5 Steroid fatty acid esters are water-insoluble molecules, which are transported in lipoprotein particles in the circulation. Unesterified steroids are incorporated in lipoproteins only to a small extent. Brodeur et al. did not discuss the possibility that the lipoprotein bound estradiol in their study could be, in fact, esterified with fatty acids. The fatty acid esterification of estradiol would be important to specify, because the esterification has been shown to enhance the potential of estradiol to protect lipoproteins from oxidation.6-8 The antioxidant protection of LDL by bound estradiol esters even after entering the arterial intima could hinder the progress of atherosclerosis, and a similar mechanism could have a role also in bone health, assuming that oxidized LDL participates in the pathogenesis of osteoporosis. It is known that estradiol becomes esterified in plasma on HDL3 particles by lecithin:cholesterol acyltransferase (LCAT) and is transferred from HDL to LDL in a process at least partly mediated by cholesteryl ester transfer protein (CETP).9, 10 In our in vitro incubations with plasma and also isolated total plasma HDL and HDL3 subfraction, under conditions similar to the ones used by Brodeur et al., estradiol associates with lipoprotein particles in mostly esterified form.3, 9 In HDL particles after plasma incubation, 83% of bound hormone was fatty acid ester and only 17% was free, unesterified E2. In isolated HDL and HDL3 subfractions, without any purification, there is still enough lipoprotein associated LCAT left to support the fatty acid esterification of estradiol.9 In serum samples from pregnant women, estradiol accumulates in lipoproteins in esterified form, and free estradiol is mostly undetectable by time-resolved fluoroimmunoassay (TR-FIA) in isolated very LDL (VLDL), LDL, and HDL fractions.11 We have also quantitated estradiol fatty acid esters in blood and adipose tissue samples from postmenopausal women, as well as premenopausal and pregnant women.12, 13 The results confirmed the abundance of these lipophilic estrogen derivatives in adipose tissue and showed that the proportion of esterified estradiol compared with free hormone is enhanced during low estrogen status. The serum estradiol ester/free ratio was lowest in pregnancy (0.5%) and increased to 15% in premenopausal women and to 110% in postmenopausal women. In postmenopausal women, the overwhelming majority of estradiol was present in adipose tissue, most of it in fatty acid ester form.13 Estradiol fatty acid esterification and hydrolysis have been described in humans and various tissues from mammals and invertebrates, showing that these mechanisms are evolutionally conserved and probably of importance.4, 14 Although the function of estradiol esters has not been clarified, they are known to have long half-lives and to display prolonged hormonal activity, which suggests a function as a reservoir for the release of active estradiol, probably by hormone sensitive lipase (HSL) present in the cytosol.15-19 The release of estradiol from its fatty acid ester form would also be a faster way to obtain active hormone compared with biosynthesis from cholesterol. The recently published results imply that the fatty acid esterification of estradiol and subsequent transportation of these esters in plasma lipoprotein particles may have an important role in the selective routing of the active hormone to target tissues, such as bone, vascular endothelium, or liver cells. It is intriguing to note that other steroid hormones, such as dehydroepiandrosterone (DHEA), pregnenolone, and Δ5-androstenediol, are esterified by LCAT, after which they become associated with HDL and are taken up by animal cells, resulting in hydrolysis of the esters and subsequent metabolic conversion of the hormones.4, 20, 21 With pregnenolone, there is also evidence of lipoprotein receptor–mediated uptake mechanism. Future studies must be designed to increase our understanding of the lipoprotein associated steroid hormone esters and their uptake into tissues, as well as to put this knowledge into use in designing therapies targeted to postmenopausal osteoporosis and atherosclerosis in particular.