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Carcinogenesis. 2019 Jun 5. pii: bgz107. doi: 10.1093/carcin/bgz107. [Epub ahead of print]

Sex hormone-binding globulin suppresses NAFLD triggered hepatocarcinogenesis after menopause.

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College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.
KM Convergence Research Division, Korea Institute of Oriental Medicine, Republic of Korea.
Kangwon National University, Chuncheon, Gangwon, Republic of Korea.
Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea.
College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.


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 five months. Fat-rich diet fed or ovariectomized (OVX) WT 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 17β-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.


HCC; NAFLD; NASH; Postmenopause; SHBG


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