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Abstract
Genistein (GEN) has been shown to significantly inhibit hepatic triglyceride accretion triggered by estrogen deficiency. The main purpose of this in vitro study was to investigate the function and molecular mechanism of estrogen receptor β (ERβ) in regulating hepatic lipid metabolism induced by GEN. Different doses of GEN or GEN with an ERβ antagonist were treated with HepG2 cells. Results showed that 25 μM GEN significantly diminished triglyceride levels. Meanwhile, GEN downregulated the levels of genes and proteins involved in lipogenesis, such as sterol-regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FASN), and stearoyl-coenzyme A desaturase 1 (SCD1), and upregulated the gene and protein levels of the regulation factors responsible for fatty acid β-oxidation, such as carnitine palmitoyltransferase 1α (CPT-1α) and peroxisome proliferator-activated receptor α (PPARα). Furthermore, 25 μM GEN reduced the levels of phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Moreover, most of these effects from GEN were reverted by pretreatment with the antagonist of ERβ. In conclusion, GEN improved hepatic lipid metabolism by activating ERβ and further modulation of Akt/mTOR signals. The results provide novel aspects of the regulatory mechanism of ERβ on hepatic lipid metabolism and might help to profoundly understand the functions of food-derived phytoestrogens in preventing and treating hepatic steatosis in postmenopausal women.
Highlights
Postmenopausal women tend to have a higher risk of developing lipid disorders due to deficient internal estrogen levels
We found that the ratios of phosphorylation of Akt and mechanistic target of rapamycin (mTOR) to total AKT and mTOR were reduced by GEN treatment, which was consistent with the regulation patterns of proteins related to lipogenic or fatty acid β-oxidation
We demonstrated that activation of estrogen receptor β (ERβ) by GEN inhibited p-Akt and p-mTOR protein expression, as well as regulated genes or proteins involved in lipid synthesis or fatty acid β-oxidation in the liver
Summary
Postmenopausal women tend to have a higher risk of developing lipid disorders due to deficient internal estrogen levels. Other research showing data from 488 postmenopausal women summarized that the duration of menopause directly impacts the severity of liver disease with increased risk of hepatic fibrosis or even hepatocarcinoma [2]. As estrogen directly influences energy homeostasis [3], hormone replacement therapy (HRT) has been utilized as a treatment for preventing postmenopausal women from developing lipid disorders [4]. It is still controversial whether HRT might be associated with an increased risk of breast and endometrial cancers [5,6]. There is still no precise pharmacotherapy approved for hepatic steatosis; researchers are implementing knowledge on food nutrition to alleviate lipid disorders [7] and to further improve quality of life, which could be an effective strategy to block the progression of hepatic steatosis in postmenopausal women
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