Key result
Treatment with the extracellular cathepsin D inhibitor CTD-002 improved hepatic steatosis, reduced inflammation, and significantly lowered plasma insulin and hepatic transaminases in high fat diet-fed rats.
Why the study?
Despite cathepsin D being implicated in NAFLD pathogenesis, the specific role of extracellular cathepsin D had not yet been investigated, while inhibiting intracellular cathepsin D is physiologically unfavorable.
Does CTD-002 improve hepatic steatosis and metabolic markers in preclinical models of NAFLD?
Does CTD-002 improve hepatic steatosis and metabolic markers in preclinical models of NAFLD?
Inhibition of extracellular cathepsin D with CTD-002 improves hepatic steatosis and metabolic parameters in preclinical models of NAFLD.
Dietary and lifestyle changes are leading to an increased occurrence of non-alcoholic fatty liver disease (NAFLD). Using a hyperlipidemic murine model for non-alcoholic steatohepatitis (NASH), we have previously demonstrated that the lysosomal protease cathepsin D (CTSD) is involved with lipid dysregulation and inflammation. However, despite identifying CTSD as a major player in NAFLD pathogenesis, the specific role of extracellular CTSD in NAFLD has not yet been investigated. Given that inhibition of intracellular CTSD is highly unfavorable due to its fundamental physiological function, we here investigated the impact of a highly specific and potent small-molecule inhibitor of extracellular CTSD (CTD-002) in the context of NAFLD. Treatment of bone marrow-derived macrophages with CTD-002, and incubation of hepatic HepG2 cells with a conditioned medium derived from CTD-002-treated macrophages, resulted in reduced levels of inflammation and improved cholesterol metabolism. Treatment with CTD-002 improved hepatic steatosis in high fat diet-fed rats. Additionally, plasma levels of insulin and hepatic transaminases were significantly reduced upon CTD-002 administration. Collectively, our findings demonstrate for the first time that modulation of extracellular CTSD can serve as a novel therapeutic modality for NAFLD.
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Khurana et al. (2019) studied Non-alcoholic fatty liver disease (NAFLD). CTD-002 (small-molecule inhibitor of extracellular cathepsin D) was evaluated on Hepatic steatosis, inflammation, cholesterol metabolism, plasma insulin, and hepatic transaminases. Treatment with the extracellular cathepsin D inhibitor CTD-002 improved hepatic steatosis, reduced inflammation, and significantly lowered plasma insulin and hepatic transaminases in high fat diet-fed rats.
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