Zhang Yan-Yu, Wang Jun-Xian, Qiao Fang, Zhang Mei-Ling, Luo Yuan, Du Zhen-Yu
LANEH, School of Life Sciences, East China Normal University, Shanghai, China.
Fish Physiol Biochem. 2024 Jun;50(3):1141-1155. doi: 10.1007/s10695-024-01327-4. Epub 2024 Feb 24.
Autophagy is a cellular process that involves the fusion of autophagosomes and lysosomes to degrade damaged proteins or organelles. Triglycerides are hydrolyzed by autophagy, releasing fatty acids for energy through mitochondrial fatty acid oxidation (FAO). Inhibited mitochondrial FAO induces autophagy, establishing a crosstalk between lipid catabolism and autophagy. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, stimulates lipid catabolism genes, including fatty acid transport and mitochondrial FAO, while also inducing autophagy through transcriptional regulation of transcription factor EB (TFEB). Therefore, the study explores whether PPARα regulates autophagy through TFEB transcriptional control or mitochondrial FAO. In aquaculture, addressing liver lipid accumulation in fish is crucial. Investigating the link between lipid catabolism and autophagy is significant for devising lipid-lowering strategies and maintaining fish health. The present study investigated the impact of dietary fenofibrate and L-carnitine on autophagy by activating Pparα and enhancing FAO in Nile tilapia (Oreochromis niloticus), respectively. The dietary fenofibrate and L-carnitine reduced liver lipid content and enhanced ATP production, particularly fenofibrate. FAO enhancement by L-carnitine showed no changes in autophagic protein levels and autophagic flux. Moreover, fenofibrate-activated Pparα promoted the expression and nuclear translocation of Tfeb, upregulating autophagic initiation and lysosomal biogenesis genes. Pparα activation exhibited an increasing trend of LC3II protein at the basal autophagy and cumulative p62 protein trends after autophagy inhibition in zebrafish liver cells. These data show that Pparα activation-induced autophagic flux should be independent of lipid catabolism.
自噬是一种细胞过程，涉及自噬体与溶酶体融合以降解受损蛋白质或细胞器。甘油三酯通过自噬水解，通过线粒体脂肪酸氧化（FAO）释放脂肪酸以供能。线粒体FAO受抑制会诱导自噬，从而在脂质分解代谢与自噬之间建立相互作用。过氧化物酶体增殖物激活受体α（PPARα）作为一种转录因子，可刺激脂质分解代谢基因，包括脂肪酸转运和线粒体FAO，同时还通过转录因子EB（TFEB）的转录调控来诱导自噬。因此，本研究探讨PPARα是否通过TFEB转录控制或线粒体FAO来调节自噬。在水产养殖中，解决鱼类肝脏脂质积累问题至关重要。研究脂质分解代谢与自噬之间的联系对于制定降脂策略和维持鱼类健康具有重要意义。本研究分别通过激活尼罗罗非鱼（Oreochromis niloticus）的Pparα和增强FAO，研究了饲料中非诺贝特和L-肉碱对自噬的影响。饲料中的非诺贝特和L-肉碱降低了肝脏脂质含量并提高了ATP生成，尤其是非诺贝特。L-肉碱增强FAO并未使自噬蛋白水平和自噬通量发生变化。此外，非诺贝特激活的Pparα促进了Tfeb的表达和核转位，上调了自噬起始和溶酶体生物发生基因。在斑马鱼肝细胞中，Pparα激活在基础自噬时使LC3II蛋白呈上升趋势，在自噬抑制后使p62蛋白呈累积趋势。这些数据表明Pparα激活诱导的自噬通量应独立于脂质分解代谢。
