Endocrine Abstracts

Autophagy is a catabolic process that promotes hepatic cell survival during starvation and metabolic stress. Currently, little is known about the endocrine regulation of autophagy. Recent studies by Singh et al. (Nature 458, 1131–1135 (2009)) showed a critical link between autophagy and beta oxidation in hepatocytes. Accordingly, we examined whether hormones known to promote beta oxidation of fatty acids also stimulated autophagy in hepatic cells. Surprisingly, we found that T3 stimulated autophagy in human hepatic cells in vitro and in mouse liver in vivo. In particular, T3 increased LC3 II and decreased p62 protein expression levels in HepG2TRalpha cells and hepatocytes. Moreover, studies using chloroquine treatment to block autophagsome/lysosome fusion and microscopic localization of RFP-GFP flurorescent tagged LC3 both demonstrated that T3 increased overall autophagic flux. Bodipy-staining and electron microscopy studies of hepatic cells showed that T3-induced autophagy remarkably involved formation of lipophagosomes that ingest lipids from fat droplets and fuse with lysosomes before fatty acid delivery to mitochondria. This T3-mediated lipophagy was also associated with increased beta-oxidation as T3 increased Cpt-1α expression. In this connection, knockdown studies using ATG5 siRNA demonstrated that T3-dependent beta oxidation of fatty acids was dependent upon autophagy. Our findings show that T3 plays a critical role in the regulation of fatty acid metabolism by co-ordinately inducing lipophagy and beta-oxidation. They also suggest that T3 or its analogs may be useful for the treatment of NAFLD, a common condition with high morbidity caused by excess fat accumulation in the livers of patients with obesity and diabetes.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.