LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver
LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver
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LGR4 作为外周生物钟和肝脏脂质代谢之间的联系
DOI：
10.1530/jme-13-0042
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Wang, Feng;Zhang, Xianfeng;Ning, Guang
生物钟通过调节能量代谢的主要方面在肝脏中起着重要作用。目前认为生物钟主要通过在转录水平上调节肝酶的表达来调节代谢，但其机制尚不清楚。在这项研究中，我们发现，Lgr 4纯合子突变（Lgr 4（m/m））小鼠显示呼吸交换率的节奏的改变。我们进一步检测到Lgr 4（m/m）小鼠的血浆甘油三酯节律受损。虽然在Lgr 4 m/m小鼠中没有观察到血浆胆固醇节律的显著变化，但它们的胆固醇水平明显降低。这种表型在ob/ob小鼠中得到进一步证实，其中缺乏LGR 4抑制甘油三酯的昼夜节律。我们接下来证明了Lgr 4表达在小鼠的肝组织和原代肝细胞中表现出昼夜节律，但我们没有检测到Lgr 4（m/m）小鼠与其同窝小鼠相比经典时钟基因（如Clock、Bmal 1（Arntl）、Pers、Rev-erbs和Crys）的表达水平或昼夜节律的变化。在与脂质代谢相关的基因中，我们发现在调节血浆脂质水平中起重要作用的Mttp基因的昼夜表达模式在Lgr 4（m/m）小鼠和原代Lgr 4（m/m）肝细胞中受损。总之，我们的研究结果表明，LGR 4在调节血浆脂质节律中起着重要作用，部分通过调节微粒体甘油三酯转移蛋白的表达。这些数据提供了外周生物钟和脂质代谢之间的可能联系。
The circadian clock plays an important role in the liver by regulating the major aspects of energy metabolism. Currently, it is assumed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level, but the underlying mechanism is not well understood. In this study, we showed that Lgr4 homozygous mutant (Lgr4(m/m)) mice showed alteration in the rhythms of the respiratory exchange ratio. We further detected impaired plasma triglyceride rhythms in Lgr4(m/m) mice. Although no significant changes in plasma cholesterol rhythms were observed in the Lgr4 m/m mice, their cholesterol levels were obviously lower. This phenotype was further confirmed in the context of ob/ob mice, in which lack of LGR4 dampened circadian rhythms of triglyceride. We next demonstrated that Lgr4 expression exhibited circadian rhythms in the liver tissue and primary hepatocytes in mice, but we did not detect changes in the expression levels or circadian rhythms of classic clock genes, such as Clock, Bmal1 (Arntl), Pers, Rev-erbs, and Crys, in Lgr4(m/m) mice compared with their littermates. Among the genes related to the lipid metabolism, we found that the diurnal expression pattern of the Mttp gene, which plays an important role in the regulation of plasma lipid levels, was impaired in Lgr4(m/m) mice and primary Lgr4(m/m) hepatocytes. Taken together, our results demonstrate that LGR4 plays an important role in the regulation of plasma lipid rhythms, partially through regulating the expression of microsomal triglyceride transfer protein. These data provide a possible link between the peripheral circadian clock and lipid metabolism.