Hypoxia tolerance of fish depends on the catabolic preference between lipid and carbohydrate

Hypoxia is a common environmental stress in aquatic organisms, which varies among fish species. However, the mechanism among fish species to tolerate hypoxia are not well known. Here we show that hypoxia response in different fish species is affected by lipid catabolism and preference for lipid or carbohydrate energy source. Biochemical lipid catabolism activation through activating peroxisome proliferators activated receptor alpha (Ppara) or increasing mitochondrial fat oxidation in tilapia decreased tolerance to acute hypoxia by increasing oxygen consumption and oxidative damage, and reducing carbohydrate catabolism as energy source. Conversely, lipid catabolism inhibition through suppressing entry of lipid into mitochondria in tilapia or individually knocking out three key genes of lipid catabolism in zebrafish increased tolerance to acute hypoxia by decreasing oxygen consumption and oxidative damage, and promoting carbohydrate catabolism. However, anaerobic glycolysis suppression eliminated lipid catabolism inhibition-promoted hypoxia tolerance in patatin-like phospholipase domain containing 2 (atgl) mutant zebrafish. In the following test using 14 fish species with different trophic levels and taxonomic status, the fish using lipid preferentially for energy source were more intolerant to acute hypoxia than those preferably utilizing carbohydrate. Our study shows that hypoxia tolerance in fish depends on catabolic preference for lipid or carbohydrate, which can be modified by regulating lipid catabolism.

低氧（hypoxia）是水生生物常见的环境胁迫因子，且在不同鱼类物种间存在差异。然而，不同鱼类耐受低氧的分子机制尚未被充分阐明。本研究发现，不同鱼类的低氧应答过程受脂质分解代谢以及脂质与碳水化合物的能量来源偏好性调控。在罗非鱼中，通过激活过氧化物酶体增殖物激活受体α（peroxisome proliferators activated receptor alpha, Ppara）或提升线粒体脂肪氧化来激活生化层面的脂质分解代谢，会通过增加耗氧量、加重氧化损伤，并减少以碳水化合物分解代谢作为能量来源的途径，从而降低其对急性低氧的耐受能力。反之，通过抑制罗非鱼体内脂质进入线粒体的过程以抑制脂质分解代谢，或是在斑马鱼中单独敲除脂质分解代谢的三个关键基因，可通过降低耗氧量、减轻氧化损伤，并促进碳水化合物分解代谢，提升其对急性低氧的耐受能力。然而，在携带patatin样磷脂酶结构域包含2（patatin-like phospholipase domain containing 2, atgl）突变的斑马鱼中，抑制无氧糖酵解会消除脂质分解代谢抑制所提升的低氧耐受能力。后续针对14种具有不同营养级和分类学地位的鱼类开展的实验表明，优先以脂质作为能量来源的鱼类，其对急性低氧的耐受能力弱于优先利用碳水化合物的鱼类。本研究表明，鱼类的低氧耐受能力取决于其对脂质或碳水化合物的分解代谢偏好性，且该偏好性可通过调控脂质分解代谢进行修饰。