Roberts Joseph L, He Bo, Erickson Anjeza, Moreau Régis
Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
Biochim Biophys Acta. 2016 Mar;1861(3):166-76. doi: 10.1016/j.bbalip.2015.12.001. Epub 2015 Dec 8.
The activation of hepatic kinase mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the development of obesity-related metabolic disorders. This study investigated the metabolic sequelae of mTORC1 hyperactivation in human hepatoma cells and the lipid-regulating mechanisms of two short-chain fatty acids: 4-phenylbutyric acid (PBA) and (R)-α-lipoic acid (LA). We created three stable cell lines that exhibit low, normal, or high mTORC1 activity. mTORC1 hyperactivation induced the expression of lipogenic (DGAT1 and DGAT2) and lipoprotein assembly (MTP and APOB) genes, thereby raising cellular triacylglyceride (TG) and exacerbating secretion of apoB-containing TG-rich lipoproteins. LYS6K2, a specific inhibitor of the p70 S6 kinase branch of mTORC1 signaling, reversed these effects. PBA and LA decreased secreted TG through distinct mechanisms. PBA repressed apoB expression (both mRNA and protein) and lowered secreted TG without mitigation of mTORC1 hyperactivity or activation of AMPK. LA decreased cellular and secreted TG by attenuating mTORC1 signaling in an AMPK-independent manner. LA did not regulate apoB expression but led to the secretion of apoB-containing TG-poor lipoproteins by repressing the expression of lipogenic genes, FASN, DGAT1, and DGAT2. Our studies provide new mechanistic insight into the hypolipidemic activity of PBA and LA in the context of mTORC1 hyperactivation and suggest that the short-chain fatty acids may aid in the prevention and treatment of hypertriglyceridemia.
肝脏激酶机制性雷帕霉素靶蛋白复合物1（mTORC1）的激活与肥胖相关代谢紊乱的发生有关。本研究调查了人肝癌细胞中mTORC1过度激活的代谢后果以及两种短链脂肪酸：4-苯基丁酸（PBA）和（R）-α-硫辛酸（LA）的脂质调节机制。我们创建了三种稳定的细胞系，分别表现出低、正常或高mTORC1活性。mTORC1过度激活诱导了脂肪生成（二酰甘油酰基转移酶1和二酰甘油酰基转移酶2）和脂蛋白组装（微粒体甘油三酯转移蛋白和载脂蛋白B）基因的表达，从而提高细胞内甘油三酯（TG）水平并加剧含载脂蛋白B的富含TG脂蛋白的分泌。LYS6K2是mTORC1信号通路中p70 S6激酶分支的特异性抑制剂，可逆转这些作用。PBA和LA通过不同机制降低分泌型TG。PBA抑制载脂蛋白B的表达（mRNA和蛋白水平）并降低分泌型TG，而不减轻mTORC1的过度激活或激活AMPK。LA以不依赖AMPK的方式减弱mTORC1信号通路，从而降低细胞内和分泌型TG。LA不调节载脂蛋白B的表达，但通过抑制脂肪生成基因脂肪酸合酶（FASN）、二酰甘油酰基转移酶1和二酰甘油酰基转移酶2的表达，导致分泌含载脂蛋白B的低TG脂蛋白。我们的研究为PBA和LA在mTORC1过度激活情况下的降血脂活性提供了新的机制见解，并表明短链脂肪酸可能有助于预防和治疗高甘油三酯血症。
