With regards to obesity and type 2 diabetes-associated NAFLD, insulin resistance in adipose tissue hinders insulin-mediated suppression of lipolysis and, thus, increases the levels of serum free fatty acids (FFA) 8. However, these treatments possess unwanted off-target effects and involve perennial dosing. Instead, current treatments act by increasing systemic insulin sensitivity such as thiazolidinediones, rosiglitazone, metformin 3, and/or approaches such as decreasing food intake, for instance GLP-1 receptor agonism (exenatide and liraglutide) 3, 5, 6, 7. Clinically today, no approved pharmacological agents target the liver directly to counteract NAFLD 3, 4. Continued decline in liver function leads to hepatocarcinoma or liver failure, where the only treatment option is a liver transplant, which has a low likelihood of success 2. Patients with untreated NAFLD subsequently develop non-alcoholic steatohepatitis with some fibrosis, which can progress to liver cirrhosis 2. NAFLD is characterized by the accumulation of lipid in the liver, and its prevalence directly correlates with obesity and insulin resistance. Non-alcoholic fatty liver disease (NAFLD) affects 20 to 30% of the world’s population 1. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy.
We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity.
High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease
0 kommentar(er)
