Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria.
Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics, University Medical Center Groningen, 9712 Groningen, The Netherlands.
Int J Mol Sci. 2021 Feb 20;22(4):2126. doi: 10.3390/ijms22042126.
Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3-PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout () mice lacking both and ; mice were compared to after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of and resulted in weight gain on a chow diet; when challenged by HFD, mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. deficiency aggravates the effects of deletion on steatosis and inflammation in the liver under HFD challenge.
改变的脂质代谢途径，包括甘油三酯的水解，是非酒精性脂肪性肝病（NAFLD）发病机制中的关键因素。脂肪素（亲脂酶结构域包含蛋白 3-PNPLA3）和单酰基甘油脂肪酶（MGL）是否协同促进疾病进展尚不清楚。我们生成了缺乏 和 的双敲除（）小鼠；将 小鼠与 小鼠进行比较，后者在高脂肪饮食（HFD）喂养 12 周后诱导脂肪变性。分析血清生化、肝转氨酶以及组织学。通过气相色谱法评估肝和脂肪组织中的脂肪酸（FA）谱。分析炎症和脂质代谢标志物。分离骨髓来源的巨噬细胞（BMDMs）并进行油酸处理。 和 联合缺失导致正常饮食时体重增加；当受到 HFD 挑战时，与 小鼠相比， 小鼠表现出增加的肝 FA 合成和减少的β氧化，表现出更明显的肝脂肪变性伴炎症和免疫细胞募集到肝脏，与饱和 FA 的积累相关。从 小鼠分离的原代 BMDMs 显示出增加的炎症活性，这可以通过油酸补充来逆转。在 HFD 挑战下， 缺失加重了 缺失对肝脂肪变性和炎症的影响。
