Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Food Chem Toxicol. 2018 Apr;114:52-60. doi: 10.1016/j.fct.2018.02.019. Epub 2018 Feb 10.
The consumption of a quercetin-rich diet has been well-established as a feasible method against non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by quercetin remain largely obscure. Male Sprague-Dawley rats fed high-fat diet (HFD), and HepG2 cells stimulated with free fatty acid, were treated with quercetin and various pharmacological reagents to explore the effect of signaling pathways involved in endoplasmic reticulum stress on very low-density lipoprotein (VLDL) assembly and lipophagy. Quercetin intake decreased hepatic TG content by 39%, with a 1.5-fold increase in VLDL, and up-regulated spliced X-box binding protein 1 (XBP1s) expression compared with the HFD group. Thapsigargin or STF-083010 (an IRE1α endonuclease inhibitor) decreased VLDL content in a dose-dependent manner, partially counteracting the protective effects of quercetin, 4-PBA or APY-29 (an IRE1α endonuclease activator). Additionally, microsomal TG-transfer protein complex expression was increased with quercetin-treated and down-regulated by STF-083010. Moreover, quercetin increased co-localization of lysosomes with lipid droplets (LDs) accompanied by decreased p62 accumulation. STF-083010 partially abolished the effect of quercetin on LDs autophagy in an mTOR-independent manner. Collectively, these findings demonstrate that hepatic VLDL assembly and lipophagy are the main targets of quercetin against NAFLD via the IRE1a/XBP1s pathway.
富含槲皮素的饮食已被证实是防治非酒精性脂肪性肝病（NAFLD）的可行方法；然而，NAFLD 进展的分子机制及其被槲皮素干预的机制在很大程度上仍不清楚。用高脂肪饮食（HFD）喂养雄性 Sprague-Dawley 大鼠，并用游离脂肪酸刺激 HepG2 细胞，用槲皮素和各种药理试剂处理这些细胞，以探讨内质网应激相关信号通路对极低密度脂蛋白（VLDL）组装和脂自噬的影响。与 HFD 组相比，槲皮素摄入使肝 TG 含量降低了 39%，VLDL 增加了 1.5 倍，并且剪接 X 盒结合蛋白 1（XBP1s）的表达增加。他普西龙或 STF-083010（IRE1α内切核酸酶抑制剂）呈剂量依赖性降低 VLDL 含量，部分抵消了槲皮素、4-PBA 或 APY-29（IRE1α内切核酸酶激活剂）的保护作用。此外，用槲皮素处理后微粒体 TG 转移蛋白复合物的表达增加，而 STF-083010 则下调了该复合物的表达。此外，槲皮素增加了溶酶体与脂滴（LDs）的共定位，同时减少了 p62 的积累。STF-083010 以 mTOR 非依赖性方式部分消除了槲皮素对 LDs 自噬的作用。综上所述，这些发现表明，通过 IRE1a/XBP1s 通路，槲皮素通过促进肝 VLDL 组装和脂自噬来治疗 NAFLD。
