Pozo-Morales Macarena, Cobham Ansa E, Centola Cielo, McKinney Mary Cathleen, Liu Peiduo, Perazzolo Camille, Lefort Anne, Libert Frédérick, Bai Hua, Rohner Nicolas, Singh Sumeet Pal
IRIBHM, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium.
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
bioRxiv. 2024 Jan 11:2024.01.10.574986. doi: 10.1101/2024.01.10.574986.
Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that while surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Further, down-regulation of FATP2 in drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionary conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.
饥饿会导致肝脏中脂滴的积累，这一现象有点违反直觉，但从果蝇到人类都存在。与过度喂养导致的脂肪肝非常相似，营养不良期间肝脏脂质积累（脂肪变性）会导致肝毒性和肝脏萎缩。在这里，我们发现虽然墨西哥丽脂鲤的表层种群会对饥饿产生这种进化上保守的反应，但同一物种抗饥饿的洞穴鱼幼虫在饥饿时不会出现脂滴积累。此外，洞穴鱼在饥饿期间对肝脏萎缩具有抗性，这为探索肝脏保护策略提供了一个独特的系统。通过对斑马鱼、表层鱼和洞穴鱼进行比较转录组学研究，我们确定脂肪酸转运蛋白slc27a2a/fatp2与脂肪肝的发展相关。在斑马鱼中对slc27a2a进行药理抑制可挽救饥饿时肝脏的脂肪变性和萎缩。此外，果蝇幼虫中FATP2的下调会抑制饥饿诱导的脂肪变性的发展，这表明该基因在营养剥夺时调节脂肪肝方面具有进化保守的重要性。总体而言，我们的研究确定了一个保守的、可药物靶向的目标，以保护肝脏在饥饿期间不发生萎缩。
