Bisphenol A induces cholesterol biosynthesis in HepG2 cells via SREBP-2/HMGCR signaling pathway

Abstract

-Bisphenol A (BPA), an environmental chemical to which humans are commonly exposed, has been shown to increase cholesterol level but the molecular mechanism is not clear. Since cholesterol biosynthesis plays an important role in elevating cholesterol level, the aim of the present study is to explore the effects of BPA on cholesterol biosynthesis in HepG2 cells and its possible mechanisms. HepG2 cells were treated with different concentrations of BPA for 24 hr, the total cholesterol level and the activity of 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) were measured using commercial enzymatic assay kits, and the mRNA and protein expression levels of sterol regulatory element binding protein-2(SREBP-2) and HMGCR were analyzed by qPCR, Western blotting and immunofluorescence, respectively. After treating HepG2 cells with different concentrations (0.1 nM~10 µM) of BPA for 24 hr, we found that BPA at the environmentally relevant concentrations of 1 nM and 10 nM significantly increased the total cholesterol content, the activity and expression of HMGCR in HepG2 cells, but at 100 nM, 1 µM and 10 µM doses, BPA had no stimulatory effect on cholesterol biosynthesis. The whole doseresponse relationship follows non-monotonic dose responses, such as an inverted U-shape. Using human SREBP-2 small interfering RNA, we further discovered that the stimulatory effects of BPA on cholesterol biosynthesis and HMGCR expression could be prevented by blockade of the SREBP-2 pathway. This study provides important implications for understanding the potential lipotoxicity of BPA exposure, and it also indicates that low-dose BPA induces hepatic cholesterol biosynthesis through upregulating the SREBP-2/HMGCR signaling pathway.

NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway with cholesterol uptake and lipogenesis inhibition

“…The enzymatic activity of HMGCR was evaluated by quantifying the NADPH extinction using HMG-CoA Reductase Activity Assay Kit (abcam, ab204701). The assay was performed as described previously ( Li et al., 2019 ). Briefly, the cells were lysated by the cell lysis buffer (20-mM Tris [pH 7.5], 150-mM NaCl, and 1% Triton X-100).…”

Endocrine Disrupting Chemicals, Hormone Receptors, and Acne Vulgaris: A Connecting Hypothesis

“…Mono-2-ethylhexyl Phthalate (MEHP), a metabolite of a widely used industrial plasticizer, was shown to promote lipogenesis and expression of SREBP-1c, ACC, FASN, and other known AR-regulated genes [61]. BPA, which like MEHP, is a AR ligand, was shown to exacerbate cholesterol synthesis through regulation of AR target genes including 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and SREBP-2 [72].…”

Exposure to Zearalenone Leads to Metabolic Disruption and Changes in Circulating Adipokines Concentrations in Pigs

“…Both LDL and HDL levels paralleled the rise in cholesterol, indicating that bidirectional cholesterol transport from liver to peripheral tissues and back was enhanced. Such effects are known for estrogens [28] and xenoestrogens [29], since these regulate liver lipid metabolism. These results, together with AST concentration changes suggest a possible disruption of liver lipid metabolism by ZEN, which should be further investigated.…”