We have developed a novel polymeric pH-activable, acidifying nanoparticle (acNP) that restores the pH of compromised lysosomes to rescue autophagic flux and cellular function in liver cells (HepG2) under lipotoxicity. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world today, affecting up to 30% of the world population. Recently, it has been found that chronic exposure of the liver cells to high levels of free fatty acids (i.e., lipotoxicity) results in impaired lysosomal acidification and inhibition of autophagy, a critical cellular maintenance mechanism, leading to the pathogenesis of NAFLD associated with insulin resistance. Although several studies have demonstrated that genetic restoration of autophagy can inhibit the development of NAFLD under high-fat diet, to date no effective therapeutic approach has been developed. In this study, we designed an acidic nanoparticle (acNP) that contains caged acid which can be released upon moderate pH changes to enable controlled acidification of the impaired lysosomes under lipotoxicity. The non-cytotoxic acNPs are taken up into the lysosomes of HepG2 cells, restore lysosomal acidity and decrease the accumulation of autophagic proteins LC3II and p62 expression levels, indicating an overall rescue of autophagic flux. The acNPs also increased insulin stimulated glucose uptake, effectively reversing insulin resistance in the liver cells under lipotoxicity. These results established a primary causative role of impaired lysosomal acidification on the de-regulation of autophagic flux and cellular function in hepatocytes, and the acNPs are of potential therapeutic interest for pathologies associated with lysosomal acidity impairment, such as NAFLD and Type II diabetes.

pH-activable polymeric nanoparticles restore pH in lysosomal dysfunctional diseases

256th National Meeting (2018)

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