Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Clinical Institute of Medical and Chemical Laboratory Diagnostics University Hospital Graz, Graz, Austria.
J Lipid Res. 2019 Jul;60(7):1284-1292. doi: 10.1194/jlr.M093369. Epub 2019 May 2.
Monoacylglycerol lipase (MGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. To examine the role of MGL in hepatic steatosis, WT and MGL KO (MGL) mice were challenged with a Western diet (WD) over 12 weeks. Lipid metabolism, inflammation, and fibrosis were assessed by serum biochemistry, histology, and gene-expression profiling of liver and adipose depots. Intestinal fat absorption was measured by gas chromatography. Primary adipocyte and 3T3-L1 cells were analyzed by flow cytometry and Western blot. Human hepatocytes were treated with MGL inhibitor JZL184. The absence of MGL protected mice from hepatic steatosis by repressing key lipogenic enzymes in liver (Srebp1c, Pparγ2, and diacylglycerol -acyltransferase 1), while promoting FA oxidation. Liver inflammation was diminished in MGL mice fed a WD, as evidenced by diminished epidermal growth factor-like module-containing mucin-like hormone receptor-like 1 (F4/80) staining and C-C motif chemokine ligand 2 gene expression, whereas fibrosis remained unchanged. Absence of MGL promoted fat storage in gonadal white adipose tissue (gWAT) with increased lipogenesis and unchanged lipolysis, diminished inflammation in gWAT, and subcutaneous AT. Intestinal fat malabsorption prevented ectopic lipid accumulation in livers of MGL mice fed a WD. In vitro experiments demonstrated increased adipocyte size/lipid content driven by PPARγ. In conclusion, our data uncover that MGL deletion improves some aspects of nonalcoholic fatty liver disease by promoting lipid storage in gWAT and fat malabsorption.
单酰甘油脂肪酶（MGL）是单酰甘油降解的限速酶。为了研究 MGL 在肝脂肪变性中的作用，WT 和 MGL 基因敲除（MGL）小鼠接受了为期 12 周的西方饮食（WD）挑战。通过血清生化、肝和脂肪组织的组织学和基因表达谱分析评估脂质代谢、炎症和纤维化。通过气相色谱法测量肠道脂肪吸收。通过流式细胞术和 Western blot 分析原代脂肪细胞和 3T3-L1 细胞。用人 MGL 抑制剂 JZL184 处理人肝细胞。MGL 的缺失通过抑制肝中的关键脂质生成酶（Srebp1c、Pparγ2 和二酰基甘油 -酰基转移酶 1），同时促进 FA 氧化，从而保护小鼠免受肝脂肪变性。在 WD 喂养的 MGL 小鼠中，肝脏炎症减少，表现为表皮生长因子样模块包含粘蛋白样激素受体样 1（F4/80）染色和 C-C 基序趋化因子配体 2 基因表达减少，而纤维化保持不变。MGL 的缺失促进了性腺白色脂肪组织（gWAT）中的脂肪储存，导致脂肪生成增加和脂肪分解不变，gWAT 和皮下脂肪组织中的炎症减少。肠道脂肪吸收不良可防止 WD 喂养的 MGL 小鼠肝脏中异位脂质积累。体外实验表明，PPARγ 驱动脂肪细胞大小/脂质含量增加。总之，我们的数据揭示了 MGL 缺失通过促进 gWAT 中的脂质储存和脂肪吸收不良改善了非酒精性脂肪性肝病的某些方面。
