Sex hormone-binding globulin suppresses NAFLD-triggered hepatocarcinogenesis after menopause
Sex hormone-binding globulin suppresses NAFLD-triggered hepatocarcinogenesis after menopause
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DOI：
10.1093/carcin/bgz107
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发表时间：
2019-08-01
期刊：
影响因子：
4.7
通讯作者：
Hong, Eui-Ju
中科院分区：
文献类型：
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作者：
Lee, Sang R.;Lee, Young Ho;Hong, Eui-Ju
人们普遍认为雄激素受体会增加患肝细胞癌（HCC）的风险，而雌激素会降低患HCC的风险。许多关于这方面的研究都涉及男性。因此，我们把注意力集中在女性身上，特别是绝经后的女性，她们通常雌激素供应有限。通过使用性激素结合球蛋白（SHBG）转基因小鼠，我们创造了一个类人的环境，并促进沉积和调节性激素。在暴露于二乙基亚硝胺以诱导HCC后，在达到40周龄时，小鼠被喂食富含脂肪的饮食5个月。高脂饮食喂养或卵巢切除（OVX）的62周龄野生型小鼠显示HCC进展，而高脂饮食喂养的SHBG小鼠或OVX SHBG小鼠显示较少的肿瘤。在富含脂肪的饮食喂养的SHBG小鼠的肝脏中，雌激素条件包括高水平的17 β-雌二醇和雌激素受体α导致脂肪生成抑制剂磷酸化乙酰辅酶A羧化酶的诱导，从而抑制脂肪肝。HCC荷瘤小鼠血浆SHBG的存在抑制了由雌激素和雌激素受体α介导的脂肪变性和炎症水平。相反，在OVX SHBG小鼠的肝脏中，在雌激素供应有限的条件下也观察到脂肪生成抑制。体外实验证实SHBG通过抑制乙酰辅酶A羧化酶水平抑制脂肪生成。总之，我们的研究结果表明，血浆SHBG可能对脂质介导的肝脏疾病有临床影响。
It is generally accepted that androgen receptors increase the risk of hepatocellular carcinoma (HCC), and that estrogen reduces risk of HCC. Many studies regarding this have involved males. We, therefore, have focused our attention on females, especially postmenopausal females, who typically have limited supplies of estrogen. By using sex hormone-binding globulin (SHBG) transgenic mice, we produced a humanoid environment, and facilitated deposition and modulation of sex hormones. After exposure to diethylnitrosamine to induce HCC and upon reaching the age of 40 weeks, mice were fed the fat-rich diet for 5 months. Fat-rich diet fed or ovariectomized (OVX) wild-type mice aged 62 weeks showed HCC progression, whereas fat-rich diet fed SHBG mice or OVX SHBG mice displayed fewer tumors. In the liver of fat-rich diet fed SHBG mice, estrogenic conditions including high levels of 17 beta-estradiol and estrogen receptor alpha led to the induction of the lipogenesis inhibitor, phosphorylated acetyl-CoA carboxylase, and consequently suppressed fatty liver. The presence of plasma SHBG in HCC bearing mice suppressed the levels of steatosis and inflammation in a process mediated by estrogens and estrogen receptor alpha. Conversely, in the liver of OVX SHBG mice, lipogenic inhibition was also observed under conditions where the supply of estrogens is limited. Through in vitro experiment, it was confirmed SHBG suppresses lipogenesis via inhibition of acetyl-CoA carboxylase level. In conclusion, our results show that plasma SHBG might have a clinical impact on lipid-mediated hepatic diseases.