Deregulated Lipid Sensing by Intestinal CD36 in Diet-Induced Hyperinsulinemic Obese Mouse Model.
Deregulated Lipid Sensing by Intestinal CD36 in Diet-Induced Hyperinsulinemic Obese Mouse Model.
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DOI：
10.1371/journal.pone.0145626
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Niot I
中科院分区：
文献类型：
--
作者：
Buttet M;Poirier H;Traynard V;Gaire K;Tran TT;Sundaresan S;Besnard P;Abumrad NA;Niot I
代谢综合征（MetS）大大增加了心血管疾病和糖尿病的风险，通常与餐后甘油三酯水平异常升高有关。我们评估了肠道合成的富含磷脂酰肌醇的脂蛋白（TRL）的代谢综合征的小鼠模型，通过喂养富含棕榈油的高脂肪饮食（HFD）。与对照小鼠相比，MetS小鼠分泌两个群体的TRL。如果在MetS小鼠肠脂质吸收开始时较小尺寸的群体占总颗粒的44%，则由于较大尺寸的TRL的分泌，其在4小时后仅占17%。由于TRL清除缺陷，MetS小鼠表现出长达3小时的餐后高血糖症加重。这些变化反映了TRL形成（MTP，L-FABP）和血液清除（ApoC 2）关键蛋白基因的脂质诱导延迟。这些异常与CD 36的脂质感知钝化相关，这通常是优化空肠形成大TRL所需的。在MetS小鼠中，与对照小鼠相比，脂质未下调CD 36。与MetS小鼠一样，用蛋白体抑制剂MG 132治疗对照组（可防止CD 36下调）导致MTP、L-FABP和ApoC 2基因表达的脂质诱导减弱。CD 36感应的缺乏是由于MetS小鼠中的高胰岛素血症。在脂质给药前对对照组进行急性胰岛素治疗可消除CD 36下调、TRL基因的脂质诱导和餐后甘油三酯（TG）降低，而对MetS小鼠进行链脲佐菌素治疗可恢复脂质诱导的CD 36降解和TG分泌。在体外，胰岛素治疗取消了CD 36介导的MTP在Caco-2细胞中的上调。总之，HFD治疗通过胰岛素介导的CD 36脂质感受抑制在脂质吸收的早期阶段损害TRL形成。这种损伤导致产生较小的TRL，从循环中缓慢清除，这可能有助于报告CD 36变体与MetS风险的相关性。
The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of intestinal lipid absorption in MetS mice, it accounted for only 17% after 4 h due to the secretion of larger size TRL. The MetS mice displayed accentuated postprandial hypertriglyceridemia up to 3 h due to a defective TRL clearance. These alterations reflected a delay in lipid induction of genes for key proteins of TRL formation (MTP, L-FABP) and blood clearance (ApoC2). These abnormalities associated with blunted lipid sensing by CD36, which is normally required to optimize jejunal formation of large TRL. In MetS mice CD36 was not downregulated by lipid in contrast to control mice. Treatment of controls with the proteosomal inhibitor MG132, which prevented CD36 downregulation, resulted in blunted lipid-induction of MTP, L-FABP and ApoC2 gene expression, as in MetS mice. Absence of CD36 sensing was due to the hyperinsulinemia in MetS mice. Acute insulin treatment of controls before lipid administration abolished CD36 downregulation, lipid-induction of TRL genes and reduced postprandial triglycerides (TG), while streptozotocin-treatment of MetS mice restored lipid-induced CD36 degradation and TG secretion. In vitro, insulin treatment abolished CD36-mediated up-regulation of MTP in Caco-2 cells. In conclusion, HFD treatment impairs TRL formation in early stage of lipid absorption via insulin-mediated inhibition of CD36 lipid sensing. This impairment results in production of smaller TRL that are cleared slowly from the circulation, which might contribute to the reported association of CD36 variants with MetS risk.