Abstract
Background & AimsThe lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in Sprague-Dawley rats with steatosis. However, the individual roles of extracellular and intracellular CTSD in NASH are not yet known. In the current study, we evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors.MethodsLow-density lipoprotein receptor knock out (Ldlr-/-) mice were fed a high-fat, high cholesterol (HFC) diet for ten weeks to induce NASH. Further, to investigate the effects of CTSD inhibition, mice were injected either with an intracellular (GA-12) or extracellular (CTD-002) CTSD inhibitor or vehicle control at doses of 50 mg/kg body weight subcutaneously once in two days for ten weeks.Results Ldlr-/- mice treated with extracellular CTSD inhibitor showed reduced hepatic lipid accumulation and an associated increase in faecal bile acid levels as compared to intracellular CTSD inhibitor-treated mice. Furthermore, in contrast to intracellular CTSD inhibition, extracellular CTSD inhibition switched the systemic immune status of the mice to an anti-inflammatory profile. In line, label-free mass spectrometry-based proteomics revealed that extra- and intracellular CTSD fractions modulate proteins belonging to distinct metabolic pathways.ConclusionWe have provided clinically translatable evidence that extracellular CTSD inhibition shows some beneficial metabolic and systemic inflammatory effects which are distinct from intracellular CTSD inhibition. Considering that intracellular CTSD inhibition is involved in essential physiological processes, specific inhibitors capable of blocking extracellular CTSD activity, can be promising and safe NASH drugs.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is an expanding global health burden
No Food and Drug Administration (FDA)-approved drugs are available for this disease [5, 6] and there is an urgent need for effective treatment options to manage the complex pathogenesis of non-alcoholic steatohepatitis (NASH)
While we successfully demonstrated the importance of extracellular cathepsin D (CTSD) activity in steatosis, the underlying mechanism of extracellular CTSD action compared to intracellular CTSD inhibition in NASHassociated hepatic inflammation was never investigated
Summary
Non-alcoholic fatty liver disease (NAFLD) is an expanding global health burden. NAFLD is an umbrella term that encompasses liver conditions ranging from steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NASH can further progress to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma [2]. The lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in SpragueDawley rats with steatosis. The individual roles of extracellular and intracellular CTSD in NASH are not yet known. We evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors
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