Mercola Brennan M, Villalobos Tatiana V, Wood Jocelyn E, Basu Ankita, Johnson Alyssa E
Louisiana State University, Department of Biological Sciences, Baton Rouge, LA 70803, USA.
Biol Open. 2025 Feb 15;14(2). doi: 10.1242/bio.061601. Epub 2025 Jan 30.
Lysosomes are digestive organelles that are crucial for nutrient sensing and metabolism. Lysosome impairment is linked to a broad spectrum of metabolic disorders, underscoring their importance to human health. Thus, lysosomes are an attractive target for metabolic disease therapies. In previous work, we discovered a novel class of tubular lysosomes that are morphologically and functionally distinct from traditionally described vesicular lysosomes. Tubular lysosomes are present in multiple tissues, are broadly conserved from invertebrates to mammals, are more proficient at degrading autophagic cargo than vesicular lysosomes, and delay signs of tissue aging when induced ectopically. Thus, triggering tubular lysosome formation presents one mechanism to increase lysosome activity and, notably, overproduction of the small lysosomal protein, SVIP, is a robust genetic strategy for triggering lysosomal tubulation on demand. In this study, we examine whether SVIP overexpression in the fly gut can suppress pathophysiological phenotypes associated with an obesogenic high-fat diet. Indeed, our results indicate that increasing SVIP expression in the fly gut reduces lipid accumulation, suppresses body mass increase, and improves survival in flies fed a high-fat diet. Collectively, these data hint that increasing lysosomal activity through induction of tubular lysosomal networks, could be one strategy to combat obesity-related pathologies.
溶酶体是消化细胞器，对营养感知和代谢至关重要。溶酶体功能受损与多种代谢紊乱有关，凸显了它们对人类健康的重要性。因此，溶酶体是代谢疾病治疗的一个有吸引力的靶点。在之前的工作中，我们发现了一类新型的管状溶酶体，其在形态和功能上与传统描述的囊泡状溶酶体不同。管状溶酶体存在于多种组织中，从无脊椎动物到哺乳动物广泛保守，比囊泡状溶酶体更擅长降解自噬货物，并且在异位诱导时可延缓组织衰老迹象。因此，触发管状溶酶体形成是增加溶酶体活性的一种机制，值得注意的是，小溶酶体蛋白SVIP的过量产生是一种强大的遗传策略，可按需触发溶酶体成管。在本研究中，我们研究了果蝇肠道中SVIP的过表达是否能抑制与致肥胖高脂肪饮食相关的病理生理表型。事实上，我们的结果表明，增加果蝇肠道中SVIP的表达可减少脂质积累，抑制体重增加，并提高高脂饮食果蝇的存活率。总的来说，这些数据表明，通过诱导管状溶酶体网络来增加溶酶体活性，可能是对抗肥胖相关病症的一种策略。
