Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy; S.I.S.A. Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy.
Pharmacol Res. 2019 Sep;147:104362. doi: 10.1016/j.phrs.2019.104362. Epub 2019 Jul 19.
Lysosomal acid lipase (LAL) is responsible for the hydrolysis of cholesteryl esters (CE) and triglycerides (TG) within the lysosomes; generated cholesterol and free fatty acids (FFA) are released in the cytosol where they can regulate their own synthesis and metabolism. When LAL is not active, as in case of genetic mutations, CE and TG accumulate in the lysosomal compartment, while the lack of release of cholesterol and FFA in the cytosol leads to an upregulation of their synthesis. Thus, LAL plays a central role in the intracellular homeostasis of lipids. Since there are no indications about the effect of different lipid-lowering agents on LAL activity, aim of the study was to address the relationship between LAL activity and the type of lipid-lowering therapy in a cohort of dyslipidemic patients. LAL activity was measured on dried blood spot from 120 patients with hypercholesterolemia or mixed dyslipidemia and was negatively correlated to LDL-cholesterol levels. Among enrolled patients, ninety-one were taking one or more lipid-lowering drugs, as statins, fibrates, ezetimibe and omega-3 polyunsaturated fatty acids. When patients were stratified according to the type of lipid-lowering treatment, i.e. untreated, taking statins or taking fibrates, LAL activity was significantly higher in those with fibrates, even after adjustment for sex, age, BMI, lipid parameters, liver function, metabolic syndrome, diabetes and statin use. In a subset of patients tested after 3 months of treatment with micronized fenofibrate, LAL activity raised by 21%; the increase was negatively correlated with baseline LAL activity. Thus, the use of fibrates is independently associated with higher LAL activity in dyslipidemic patients, suggesting that the positive effects of PPAR-α activation on cellular and systemic lipid homeostasis can also include an improved LAL activity.
溶酶体酸性脂肪酶（LAL）负责水解溶酶体中的胆固醇酯（CE）和甘油三酯（TG）；生成的胆固醇和游离脂肪酸（FFA）被释放到细胞质中，在那里它们可以调节自身的合成和代谢。当 LAL 没有活性时，例如在基因突变的情况下，CE 和 TG 在溶酶体腔内积聚，而胆固醇和 FFA 在细胞质中的释放不足会导致它们的合成上调。因此，LAL 在细胞内脂质平衡中起着核心作用。由于没有关于不同降脂药物对 LAL 活性的影响的迹象，因此本研究旨在探讨脂代谢紊乱患者队列中 LAL 活性与降脂治疗类型之间的关系。在 120 例高胆固醇血症或混合性血脂异常患者的干血斑上测量 LAL 活性，发现其与 LDL-胆固醇水平呈负相关。在所纳入的患者中，91 例正在服用一种或多种降脂药物，如他汀类药物、贝特类药物、依折麦布和ω-3 多不饱和脂肪酸。当根据降脂治疗类型对患者进行分层，即未治疗、服用他汀类药物或服用贝特类药物时，服用贝特类药物的患者的 LAL 活性明显更高，即使在调整性别、年龄、BMI、血脂参数、肝功能、代谢综合征、糖尿病和他汀类药物使用后也是如此。在一组接受米诺贝特治疗 3 个月后的患者中，LAL 活性升高了 21%；这种增加与基线 LAL 活性呈负相关。因此，在脂代谢紊乱患者中，贝特类药物的使用与更高的 LAL 活性独立相关，这表明 PPAR-α 激活对细胞和全身脂质平衡的积极影响还可以包括改善 LAL 活性。
