Compromised COPII vesicle trafficking leads to glycogenic hepatopathy.

Abstract

Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.