Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain and Walloon Excellence in Life Sciences and Biotechnology , Brussels , Belgium.
Am J Physiol Endocrinol Metab. 2019 Jul 1;317(1):E99-E108. doi: 10.1152/ajpendo.00082.2019. Epub 2019 Apr 30.
This study aimed to investigate the function of hepatic myeloid differentiation primary response gene 88 (MyD88), a central adaptor of innate immunity, in metabolism. Although its role in inflammation is well known, we have recently discovered that MyD88 can also mediate energy, lipid, and glucose metabolism. More precisely, we have reported that mice harboring hepatocyte-specific deletion of (Myd88) were predisposed to glucose intolerance, liver fat accumulation, and inflammation. However, the molecular events explaining the onset of hepatic disorders and inflammation remain to be elucidated. To investigate the molecular mechanism, Myd88 and wild-type (WT) mice were challenged by two complementary approaches affecting liver lipid metabolism and immunity. The first approach consisted of a short-term exposure to high-fat diet (HFD), whereas the second was an acute LPS injection. We discovered that upon 3 days of HFD Myd88 mice displayed an increase in liver weight and liver lipids compared with WT mice. Moreover, we found that bile acid and oxysterol metabolism were deeply affected by the absence of hepatic MyD88. Our data suggest that the negative feedback loop suppressing bile acid synthesis was impaired (i.e., ERK activity was decreased) in Myd88 mice. Finally, the predisposition to inflammation sensitivity displayed by Myd88 mice may be caused by the accumulation of 25-hydroxycholesterol, an oxysterol linked to inflammatory response and metabolic disorders. This study highlights the importance of MyD88 on both liver fat accumulation and cholesterol-derived bioactive lipid synthesis. These are two key features associated with metabolic syndrome. Therefore, investigating the regulation of hepatic MyD88 could lead to discovery of new therapeutic targets.
本研究旨在探究肝脏髓样分化初级反应基因 88（MyD88）的功能，MyD88 是先天免疫的核心衔接蛋白。虽然其在炎症中的作用已众所周知，但我们最近发现 MyD88 还可以介导能量、脂质和葡萄糖代谢。更确切地说，我们已经报道了肝细胞特异性缺失 （Myd88） 的小鼠易患葡萄糖不耐受、肝脂肪积累和炎症。然而，解释肝脏紊乱和炎症发生的分子事件仍有待阐明。为了研究分子机制，我们用两种互补的方法来挑战 Myd88 和野生型（WT）小鼠，这两种方法都影响肝脏的脂质代谢和免疫。第一种方法是短期暴露于高脂肪饮食（HFD），第二种方法是急性 LPS 注射。我们发现，在 HFD 喂养 3 天后，Myd88 小鼠的肝脏重量和肝脏脂质含量均高于 WT 小鼠。此外，我们发现胆汁酸和氧化固醇代谢也受到肝脏 MyD88 缺失的深刻影响。我们的数据表明，抑制胆汁酸合成的负反馈回路在 Myd88 小鼠中受损（即 ERK 活性降低）。最后，Myd88 小鼠对炎症敏感性的易感性可能是由于 25-羟胆固醇（一种与炎症反应和代谢紊乱相关的氧化固醇）的积累所致。本研究强调了 MyD88 对肝脏脂肪积累和胆固醇衍生生物活性脂质合成的重要性。这两个特征与代谢综合征密切相关。因此，研究肝脏 MyD88 的调控可能会发现新的治疗靶点。
