Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway

Nonalcoholic fatty liver disease (NAFLD) is a serious health problem. Although NAFLD represents a form of lipotoxicity, its pathogenesis remains poorly understood. The aim of this study was to examine the cellular mechanisms involved in free fatty acid (FFA)-mediated hepatic lipotoxicity. FFA treatment of liver cells resulted in Bax translocation to lysosomes and lysosomal destabilization with release of cathepsin B (ctsb), a lysosomal cysteine protease, into the cytosol. This process was also partially dependent on ctsb. Lysosomal destabilization resulted in nuclear factor κB-dependent tumor necrosis factor α expression. Release of ctsb into the cytoplasm was also observed in humans with NAFLD and correlated with disease severity. In a dietary murine model of NAFLD, either genetic or pharmacological inactivation of ctsb protected against development of hepatic steatosis, liver injury, and insulin resistance with its associated “dysmetabolic syndrome.” In conclusion , these data support a lipotoxic model of FFA-mediated lysosomal destabilization. Supplemental material for this article can be found on the Hepatology website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (Hepatology 2004;40:185-194.)