Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation

Abstract

Autophagy is a fundamental housekeeping process by which cells degrade their components to maintain homeostasis. Defects in autophagy have been associated with aging, neurodegeneration and metabolic diseases. Non-alcoholic fatty liver diseases (NAFLDs) are characterized by hepatic fat accumulation with or without inflammation. No treatment for NAFLDs is currently available, but autophagy induction has been proposed as a promising therapeutic strategy. Here, we aimed to design autophagy-inducing particles, using the autophagy-inducing peptide (Tat-Beclin), and achieve liver targeting in vivo, taking NAFLD as a model disease. Polylactic acid (PLA) particles were prepared by nanoprecipitation without any surfactant, followed by surface peptide adsorption. The ability of Tat-Beclin nanoparticles (NP T-B) to modulate autophagy and to decrease intracellular lipid was evaluated in vitro by LC3 immunoblot and using a cellular model of steatosis, respectively. The intracellular localization of particles was evaluated by transmission electron microscopy (TEM). Finally, biodistribution of fluorescent NP T-B was evaluated in vivo using tomography in normal and obese mice. The results showed that NP T-B induce autophagy with a long-lasting and enhanced effect compared to the soluble peptide, and at a ten times lower dose. Intracellular lipid also decreased in a cellular model of NAFLD after treatment with T-B and NP T-B under the same dose conditions. Ultrastructural studies revealed that NP T-B are internalized and located in endosomal, endolysosomal and autolysosomal compartments, while in healthy and obese mice, NP T-B could accumulate for several days in the liver. Given the beneficial effects of autophagy-inducing particles in vitro, and their capacity to target the liver of normal and obese mice, NP T-B could be a promising therapeutic tool for NAFLDs, warranting further in vivo investigation.

Autophagy: A Cellular Guardian against Hepatic Lipotoxicity

“…These are molecules that specifically target a known protein involved in the autophagy pathway. One such molecule is Tat-beclin 1 (Tat-BECN1), a peptide known to stimulate autophagy through mobilization of endogenous Beclin 1 [ 95 ]. Other molecules in this class of drugs are TFEB activators [ 96 ] and ULK1 activators [ 97 ], but their role in regulating hepatic lipotoxicity remains to be investigated.…”

Autophagy and senescence of rat retinal precursor cells under high glucose

“…Previous studies mainly focused on pericytes and RPE cells' autophagy in DR. Wang et al (17) found that the high expression of the autophagy-related gene (ARG) MAPK3 in retinal pigment epithelial cells might be involved in outer bloodretina barrier destruction in DR. Lin et al (18) described in detail the effect of oxidative stress-activated autophagy on RGCs; however, it remains controversial whether the autophagy in RGCs is beneficial. It is worth noting that there is increasing evidence that autophagy is related to senescence, another common pathological change in endocrine and neurological diseases (19)(20)(21). Conclusively, the role of the double-edged sword of autophagy in DR is complicated; particularly significant is that the role and mechanism of RGCs autophagy in hyperglycemia and DR remain unclear.…”