Inflammatory stress exacerbates hepatic cholesterol accumulation via disrupting cellular cholesterol export |
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Authors: | Chen Yuyang Chen Yao Zhao Lei Chen Yaxi Mei Mei Li Qing Huang Ailong Varghese Zac Moorhead John F Ruan Xiong Z |
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Affiliation: | Chongqing Key Laboratory of Lipid and Glucose Metabolism, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. |
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Abstract: | Background and Aim: Both inflammation and cholesterol accumulation play important roles in the development of non‐alcoholic fatty liver disease. This study was undertaken to investigate whether inflammation aggravated cholesterol accumulation via disrupting hepatic cholesterol export and we explored the underlying mechanisms. Methods: We used casein injection in C57BL/6J mice, and tumor necrosis factor alpha (TNF‐α) stimulation in human hepatoblastoma cell line (HepG2) cells to induce inflammation. Intracellular cholesterol level was examined by Oil Red O staining and quantitative analysis. Bile acid level was quantified by colorimetric analysis. 3[H] cholesterol assay by scintillation counting was performed to evaluate the cholesterol efflux. The mRNA and protein expression was examined by real‐time polymerase chain reaction and Western blot. Results: Inflammation increased cholesterol accumulation in livers of C57BL/6J mice and in HepG2 cells. High‐fat diet in mice and low‐density lipoprotein (LDL) loading in HepG2 cells increased bile acid synthesis and cholesterol efflux, enhanced the mRNA and protein expression of liver X receptor α (LXRα), peroxisome proliferator‐activated receptors (PPARα, γ), cholesterol 7α‐hydroxylase (CYP7A1) and ATP‐binding cassette transporter A1 (ABCA1). However, inflammation reduced bile acid synthesis and cholesterol efflux even in high‐fat‐diet‐fed mice and HepG2 cells in the presence of LDL loading. The enhanced effects of these genes and proteins expression due to high‐fat diet and LDL loading were inhibited by inflammation both in vivo and in vitro. Conclusions: Inflammation disrupted PPAR‐LXR‐CYP7A1/ABCA1‐mediated bile acid synthesis and cholesterol efflux resulting in exacerbated cholesterol accumulation in livers of C57BL/6J mice and HepG2 cells. |
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Keywords: | bile acid cholesterol efflux fatty liver inflammation liver X receptor α |
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