Lysosomal degradation of lipids and proteins and method of use thereof
Inventors
Alipour, Mohsen Amir • Yao, Zemin
Assignees
Publication Number
US-11298402-B2
Publication Date
2022-04-12
Expiration Date
2036-07-08
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Abstract
Methods for modulating lysosome-mediated microautophagy of a lipid or protein substrate in a cell are provided herein. In certain embodiments, said methods may comprise increasing lysosome-mediated microautophagy by treating the cell with a microautophagy-enhancing agent which increases lysosomal association-dissociation events between lysosomes and the cellular lipid or protein substrate and/or increases lysosomal degradation capacity; or decreasing lysosome-mediated microautophagy by treating the cell with a microautophagy-reducing agent which reduces lysosomal association-dissociation events between lysosomes and the cellular lipid or protein substrate and/or decreases lysosomal degradation capacity; thereby modulating lysosome-mediated microautophagy of the lipid or protein substrate.
Core Innovation
The invention relates to methods for modulating lysosome-mediated microautophagy of lipid or protein substrates in cells by increasing or decreasing lysosomal association-dissociation (kiss-and-run) events and/or lysosomal degradation capacity. The methods comprise treating cells with microautophagy-enhancing or microautophagy-reducing agents that respectively increase or decrease lysosomal interaction with lipid or protein substrates, thereby modulating lysosome-mediated microautophagy.
The problem being solved is the unclear cellular pathway through which omega-3 fatty acids reduce lipid levels, hindering development of therapeutic treatments effective against conditions related to elevated cytosolic lipid droplets (CLDs) and/or triglyceride levels. High triglyceride levels can cause lipotoxicity and organ damage linked to liver and cardiovascular diseases. Current methods for reducing intracellular lipid or protein content are insufficient, and alternative or improved compositions and methods are desirable.
The invention identifies specific agents including omega-3 fatty acids, Arl8b protein variants (GDP- or GTP-bound forms), and HOPS complex subunits that can modulate lysosome-mediated microautophagy. It demonstrates that lysosomal motility and the dynamics of lysosome-substrate interactions govern microautophagy, providing novel strategies to increase or decrease degradation of lipid droplets or protein aggregates in cells relevant to diseases such as hypertriglyceridemia, fatty liver disease, hepatitis C virus infection, Parkinson's disease, obesity, and liver cancer.
Claims Coverage
The patent discloses two independent claims focusing on methods of increasing lysosome-mediated microautophagy and methods for treating metabolic and infectious diseases by administering specific polypeptides.
Method of increasing lysosome-mediated microautophagy in hepatic cells by polypeptide administration
Administering a polypeptide consisting of the amino acid sequence of Arl8bT34N (SEQ ID NO: 12) to increase lysosome-mediated microautophagy of a lipid or protein substrate in a hepatic cell.
Treatment of metabolic and infectious diseases by polypeptide administration
Administering a polypeptide comprising the amino acid sequence of Arl8bT34N (SEQ ID NO: 12) to a subject to treat conditions including hypertriglyceridemia, hepatosteatosis, non-alcoholic fatty liver disease (NAFLD), hepatitis C virus (HCV) infection, hyperglycemia, hepatic insulin insensitivity, or obesity by increasing lysosome-mediated microautophagy.
The claims cover methods of enhancing lysosome-mediated microautophagy in hepatic cells by administering the specific Arl8bT34N polypeptide and treating metabolic and infectious disorders by such administration to a subject. The focus is on modulating lysosomal microautophagy using the polypeptide defined by its amino acid sequence.
Stated Advantages
Microautophagy-enhancing agents like omega-3 fatty acids and Arl8bT34N accelerate lysosome-mediated degradation of lipid droplets and proteins.
Activating microautophagy restores lysosomal motility and improves cellular lipid and protein turnover, which may ameliorate diseases related to lipid and protein accumulation.
The approach enables modulation of microautophagy distinct from classical macroautophagy, offering potentially improved therapeutic options.
Microautophagy modulation may be protective against or treat metabolic conditions like fatty liver disease, hypertriglyceridemia, hyperglycemia, and obesity, as well as neurological diseases such as Parkinson's and viral infections like hepatitis C.
Use of Arl8bT34N prevents steatosis and obesity in animal models, indicating therapeutic potential.
Documented Applications
Treatment or prevention of hypertriglyceridemia, hepatosteatosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatitis C virus (HCV) infection, hyperglycemia, hepatic insulin insensitivity, obesity, Parkinson's disease, liver cancer, and associated metabolic and neurodegenerative disorders.
Use in enhancing or decreasing lysosome-mediated microautophagy to modulate cellular lipid or protein content, relevant to diseases characterized by lipid or protein accumulation.
Cell culture and animal models with controllable hepatosteatosis for identifying biomarkers, therapeutic treatments, or delivery agents for hepatosteatosis-related diseases.
Screening and identification of microautophagy-enhancing or reducing agents for therapeutic applications.
Use in preventing or reducing fatty liver and liver failure induced by total parenteral nutrition.
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