Fig. 8: TFEB regulation of hepatic lipid metabolism and antioxidant defense.

TFEB is a nutrient and stress-sensing transcriptional factor that plays an important role in regulating cellular metabolic homeostasis. This study shows that TFEB, via activation of the hepatic autophagy-lysosomal proteolysis and induction of sulfur amino acid flux, increases hepatic cysteine availability that drives downstream CoA, GSH and taurine synthesis. In addition, previous studies show that TFEB, partly via PGC1α induction, promotes PPARα activation and fatty acid oxidation. Under NAFLD condition, incomplete fatty acid oxidation produces ROS to increase oxidative stress and mitochondrial dysfunction. This study shows that TFEB mediates the synthesis of GSH that enhances hepatic antioxidant defense and redox homeostasis. Previous study reports that TFEB induces bile acid synthesis to lower cholesterol. TFEB-mediated cysteine enrichment also drives the synthesis of taurine, which supports bile acid conjugation and homeostasis. In summary, this study reveals TFEB regulation of hepatic sulfur amino acid metabolism that links TFEB to control of hepatic metabolic and redox homeostasis. SAMe S-adenosylmethionine, MAT Methionine adenosyltransferase, CoA coenzyme A, GSH reduced glutathione, PPARα peroxisome proliferator-activated receptor α, PGC1α PPARγ coactivator α.