The divergent findings between the two studies may be secondary to differences in what constituted a nutritionally deprived

cell-culture medium. The findings from this study elevate the importance of the lysosome in autophagy from a passive dumping site for autophagosomal contents to an actively regulated component of the autophagic process. Coordinated selleck chemicals up-regulation of both lysosomes and autophagosomes might prevent the problem of generating too many cargo-filled autophagosomes that overwhelm the degradative capacity of lysosomes. A mismatch between the numbers of autophagosomes and lysosomes could have dire consequences for the cell. The study emphasizes the need to focus more on whether defects in autophagy are secondary to lysosomal problems and, possibly, TFEB. Steatosis inhibits autophagic function in hepatocytes, 10 and this decrease in autophagy has been attributed to both defects in autophagosome/lysosome fusion 11 and

decreased expression of ATGs. 12 It is possible that defects in TFEB regulation contribute to a multifactorial impairment in autophagic function in fatty liver disease. The study by Settembre et al. 7 also delineates another critical selleck screening library function for MAPK signaling. Studies in nonhepatic cells have shown that the MAPK c-Jun N-terminal kinase (JNK) up-regulates autophagy through phosphorylation of Bcl-2 family members, 13 although the existence of this pathway in hepatocytes, which lack Bcl-2, remains unproven. ERK1/2 and JNK, which are frequently activated in tandem by cellular stresses, may counterbalance each other’s effect on autophagy. That

ERK1/2 down-regulates autophagy contradicts the concept see more of ERK1/2 signaling as cytoprotective, because autophagy generally promotes survival. Interestingly, although oxidant stress is considered a major inducer of autophagy, hepatocyte oxidant stress associated with ERK1/2 activation failed to increase levels of autophagy. 14 The effects of JNK and ERK1/2 on autophagic function specifically in hepatocytes need to be examined. The study does not provide direct evidence that endogenous TFEB regulates hepatocyte autophagy in vivo; however, this is likely given the strong evidence of TFEB function and TFEB’s high expression in liver. 15 However, hepatocyte knockout/knockdown studies of TFEB need to be performed. Whether TFEB mediates increases in autophagy to stimuli other than starvation also needs to be examined. Recently, a chemical stimulator of autophagy has been shown to be an effective treatment for murine α1-antitrypsin deficiency. 16 A number of other hepatic diseases, including nonalcoholic and alcoholic fatty liver disease, viral hepatitis, and liver cancer, may benefit from autophagy-directed therapies. 1 By establishing a central role for TFEB in the regulation of autophagy, this study identifies this protein as a potential therapeutic target.