Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway.
Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway.
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DOI：
10.1016/j.freeradbiomed.2021.06.027
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发表时间：
2021-06
影响因子：
7.4
通讯作者：
Ping Li;Xiu Chen;Minlei Dong;Jun Luo;Shuanghui Lu;Mingyang Chen;Yingqiong Zhang;Hui Zhou;Huidi Jiang
中科院分区：
文献类型：
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作者：
Ping Li;Xiu Chen;Minlei Dong;Jun Luo;Shuanghui Lu;Mingyang Chen;Yingqiong Zhang;Hui Zhou;Huidi Jiang
非酒精性脂肪性肝病（NAFLD）越来越多地在病因不明的炎症性肠病（IBD）患者中发现。在目前的研究中，我们评估了结肠炎症对NAFLD发展的贡献以及IBD小鼠模型的潜在机制。我们的研究结果表明，葡聚糖硫酸钠（DSS）诱导的肠道结肠炎直接导致肝脏炎症，损伤，并进一步加剧了高脂饮食（HF）喂养引起的肝脏脂肪变性。必需基因评估、肝脏代谢分析和富含甘油三酯的极低密度脂蛋白（VLDL-TG）分泌测定显示，DSS处理的小鼠肝脏中脂肪酸（FAs）的β-氧化增加，但VLDL-TG分泌受损。DSS破坏肠道屏障，促进肝脏炎症反应，强烈抑制肝脏VLDL-TG分泌，并通过下调载脂蛋白B（APOB）进一步加重HF诱导的VLDL-TG分泌障碍，从而促进甘油三酯（TG）在肝脏的储存。混合促炎细胞因子或LPS诱导的炎症反应可明显抑制小鼠原代肝细胞微粒体甘油三酯转移蛋白（MTP）和APOB的表达，并使TG含量增加，而HNF 4 α则可抑制这种抑制作用。此外，促炎细胞因子对MTP和APOB的下调作用也可通过皮质醇激活Hnf 4 α而得到恢复。总之，我们的研究结果表明，慢性炎症通过HNF 4 α途径抑制肝脏VLDL-TG的分泌而加重肝脏脂肪变性，提示恢复肝脏VLDL-TG的分泌可能是治疗IBD中NAFLD的新策略。
Nonalcoholic fatty liver disease (NAFLD) is increasingly identified in inflammatory bowel disease (IBD) patients with unclear etiology. In the current study we assessed the contribution of colonic inflammation to NAFLD development and the underlying mechanism in a mouse model for IBD. Our results showed that dextran sulfate sodium (DSS)-induced gut colitis directly led to hepatic inflammation, injury and further exacerbated hepatic steatosis caused by high fat diet (HF) feeding. The essential genes assessment, hepatic metabolic analysis and triglyceride-rich very low-density lipoprotein (VLDL-TG) secretion assays revealed a higher β-oxidation of fatty acids (FAs) but impaired VLDL-TG secretion in liver of DSS-treated mice. Disruption of the intestinal barrier by DSS promoted liver inflammation, which strongly suppressed hepatic VLDL-TG secretion and further aggravated HF-induced VLDL-TG secretion impairment through down-regulation of apolipoprotein B (APOB), hence promoting the storage of triglycerides (TG) in the liver. Inflammation induced by mixed proinflammatory cytokines or LPS obviously inhibited the expression of microsomal triglyceride transfer protein (MTP) and APOB expression and subsequently increased TG contentviathe suppression of HNF4α in mouse primary hepatocytes. In addition, the downregulation of MTP and APOB by proinflammatory cytokines was also rescued through activating Hnf4α by cortisol. Altogether, our results demonstrated that chronic inflammation exacerbated hepatic steatosis by inhibiting the secreting of hepatic VLDL-TG through HNF4α pathway, suggesting that restoring hepatic VLDL-TG secretion may be a novel strategy for treatment of NAFLD in IBD.