Roles and regulations of starvation-induced hepatic steatosis in zebrafish

During starvation, animals utilize the liver as lipid storage organ. For instance, patients suffering from anorexia nervosa, overnight fasted mice and starved zebrafish larvae develop fatty liver. However, the mechanisms underlying starvation-induced liver damage remain unknown. Further, it remains unclear if the resolution of hepatic steatosis is beneficial to the liver and the animal. Here, we investigated the role and regulation of starvation-induced hepatic steatosis using zebrafish (Danio rerio) as model system. By in vivo imaging of calcium and lipid droplets, we published a work showing negative correlation between the two. Using a genetically encoded calcium chelator (SpiCee), we showed that buffering of calcium signaling reduces the turnover of lipid droplets. On the other hand, we increased calcium transients in the liver by mobilization of endo-lysosomal Ca2+ stores, using selective two-pore complex 2 (TPC2) agonists. This led to a resolution of hepatic lipids. Thus, we established methods to manipulate starvation-induced hepatic steatosis by modulating Ca2+ signaling. Using this system, we investigated the impact of hepatic lipid droplet accumulation, and their turnover on the health of the organ and organism. Increasing Ca2+ flux by pharmacological activation of TPC2 channels efficiently reduced fat in the zebrafish liver. However, this process enhanced macrophage infiltration, hepatocyte phagocytosis and starvation-induced mortality. On the other hand, buffering cytoplasmic Ca2+ reduced lipid droplet turnover during starvation, leading to reduced liver inflammation and increased the lifespan of starved animals. With this, we propose that fatty liver helps with starvation resistance, while hepatic lipid flux (turnover) damages the liver. To understand how animals with enhanced starvation resistance deal with hepatic steatosis and liver damage, we investigated the starvation response in cavefish (Astyanax mexicanus) in collaboration with Dr. Nicolas Rohn
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished