Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation
Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation
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DOI：
10.1016/j.bbalip.2019.01.007
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发表时间：
2019-04-01
影响因子：
4.8
通讯作者：
Kratky, Dagmar
中科院分区：
文献类型：
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作者：
Leopold, Christina;Duta-Mare, Madalina;Kratky, Dagmar
溶酶体酸性脂肪酶 (LAL) 水解胆固醇酯 (CE) 和甘油三酯 (TG)，生成脂肪酸 (FA) 和胆固醇。人类和小鼠的 LAL 缺乏症 (LAL-D) 都会导致肝肿大、高胆固醇血症和寿命缩短。尽管 LAL 在溶酶体中性脂质分解代谢中发挥重要作用，但 LAL 对疾病进展的细胞类型特异性贡献仍然难以捉摸。为了更详细地研究 LAL 在肝脏中的作用并排除 LAL 在巨噬细胞中的作用，我们培育了肝细胞特异性 LAL 缺陷小鼠 (Liv-Lipa(-/-))，并给它们喂食或高脂肪/高胆固醇饮食 (HF/HCD)。与全身性 LAL-D 相比，Liv-Lipa(-/-) 小鼠对饮食诱导的肥胖具有抵抗力，与食物摄入、运动和能量消耗无关。体重增加减少主要是由于白色脂肪组织库减少。此外，与对照小鼠相比，Liv-Lipa(-/-) 小鼠在葡萄糖和胰岛素耐量测试期间表现出改善的葡萄糖清除率。肝脏脂质含量分析显示，TG 大量减少，而 CE 浓度显着增加，导致 Liv-Lipa(-/-) 小鼠肝脏中形成 CE 晶体。血浆转氨酶活性升高、促炎细胞因子和趋化因子增加以及肝巨噬细胞浸润表明肝脏炎症。我们的数据提供证据表明，肝细胞特异性 LAL 缺乏足以改变小鼠的全身脂质和能量稳态。我们得出的结论是，肝脏 LAL 通过预防肝损伤和维持脂质和能量稳态发挥着关键作用，特别是在脂质利用率较高的情况下。
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa(-/-)) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa(-/-) mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa(-/-) mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa(-/-) mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability.