Altered fatty acid distribution in lysosome-associated membrane protein-2 deficient mice

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemistry and Biophysics Reports Pub Date : 2024-09-05 DOI:10.1016/j.bbrep.2024.101822
Ziming Xu , Shoji Notomi , Guannan Wu , Yosuke Fukuda , Yusuke Maehara , Masatoshi Fukushima , Yusuke Murakami , Masatomo Takahashi , Yoshihiro Izumi , Koh-Hei Sonoda
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Abstract

Lysosome-associated membrane protein-2 (LAMP2) deficiency causes the human Danon disease and represents a lysosomal dysfunction because of its pivotal role in regulating autophagy and lysosome biogenesis. LAMP2-deficient mice exhibit a spectrum of phenotypes, including cardioskeletal myopathy, mental retardation, and retinopathy, similar to those observed in patients with Danon disease. Its pathology is thought to involve altered energy metabolism and lipid dysregulation; however, the lipidomic profiles of LAMP2-deficient animals have not been investigated. In this study, we investigated lipid alterations in LAMP2 KO mice tissues, including those of the liver, plasma, and retina, using liquid chromatography-mass spectrometry. Our results revealed significantly increased free fatty acid (FFA) levels and decreased in triglyceride (TG) levels in LAMP2 KO liver tissues at three and six months. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species significantly decreased in LAMP2 KO mice livers at six months. Similarly, plasma TG and PC/PE levels decreased in LAMP2 KO mice. In contrast, plasma FFA levels were significantly lower in LAMP2 KO mice. Retina FFA levels were elevated in LAMP2 KO mice, accompanied by a partial decrease in PC/PE at six months. In summary, FFA levels increased in several tissues but not in the LAMP2 KO mice plasma, suggesting the potential consumption of FFA as an energy source in the peripheral tissues. The depletion of TG and PC/PE accelerated with age, suggesting an underlying age-dependent energy crisis condition. Our findings underscore the dysregulated distribution of fatty acids in LAMP2-deficient animals and provide new mechanistic insights into the pathology of Danon disease.

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溶酶体相关膜蛋白-2 缺陷小鼠体内脂肪酸分布的改变
溶酶体相关膜蛋白-2(LAMP2)缺乏症会导致人类达农病,由于它在调节自噬和溶酶体生物生成方面起着关键作用,因此是一种溶酶体功能障碍。LAMP2 缺陷小鼠表现出一系列表型,包括心肌肌病、智力迟钝和视网膜病变,与达农病患者的表现类似。其病理被认为涉及能量代谢的改变和脂质失调;然而,尚未对 LAMP2 基因缺陷动物的脂质组特征进行研究。在本研究中,我们使用液相色谱-质谱法研究了 LAMP2 KO 小鼠组织中的脂质变化,包括肝脏、血浆和视网膜组织。结果发现,LAMP2 KO小鼠肝脏组织中游离脂肪酸(FFA)水平在三个月和六个月后明显升高,甘油三酯(TG)水平则明显下降。六个月后,LAMP2 KO小鼠肝脏中磷脂酰胆碱(PC)和磷脂酰乙醇胺(PE)的种类明显减少。同样,LAMP2 KO 小鼠的血浆 TG 和 PC/PE 水平也有所下降。相反,LAMP2 KO 小鼠血浆中的 FFA 水平明显降低。LAMP2 KO 小鼠视网膜中的 FFA 水平升高,6 个月时 PC/PE 水平部分下降。总之,一些组织中的 FFA 水平升高,但 LAMP2 KO 小鼠血浆中的 FFA 水平并没有升高,这表明外周组织可能消耗 FFA 作为能量来源。随着年龄的增长,TG 和 PC/PE 的消耗速度加快,这表明存在潜在的年龄依赖性能量危机。我们的发现强调了脂肪酸在 LAMP2 缺乏动物体内的分布失调,并为达农病的病理机制提供了新的见解。
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来源期刊
Biochemistry and Biophysics Reports
Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics
CiteScore
4.60
自引率
0.00%
发文量
191
审稿时长
59 days
期刊介绍: Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.
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