AIM Protein Therapeutic for NASH Pathology via High-Fat Diet Model
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Solution Overview
Problem
Current treatments for non-alcoholic steatohepatitis (NASH) and related hepatic diseases lack an established method, with unclear onset mechanisms and ineffective animal models that fail to accurately replicate human pathology, hindering the development of effective therapeutic drugs.
Innovation Solution
The use of AIM (Apoptosis Inhibitor of Macrophage) or its partial peptides, or nucleic acids encoding AIM, as a prophylactic or therapeutic agent, along with a method involving AIM knockout mice on a high-fat diet to screen and evaluate substances for treating hepatic diseases, including NASH, cirrhosis, and liver cancer, by observing liver weight, fat amount, fibrosis, and inflammation response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional animal models (MCD diet or carbon tetrachloride loaded mice) are used to study NASH, then liver necrosis and fibrosis can be induced, but the model does not accurately replicate human NASH pathology caused by obesity and overnutrition
Solution Approach 1:
The patent changes the dietary parameters from conventional MCD or carbon tetrachloride models to a high-fat diet model that replicates human metabolic syndrome conditions. This parameter change enables the animal model to accurately replicate human NASH pathology caused by obesity and overnutrition, improving both reliability and adaptability to human disease.
Solution Approach 2:
The patent creates an animal model that copies the essential features of human NASH pathology including obesity, fatty liver, chronic inflammation, and insulin resistance. By using AIM knockout mice on high-fat diet, the model reproduces the key pathological characteristics of human disease while maintaining experimental tractability.
2Reliability
If AIM is suppressed in the body, then obesity-related chronic inflammation and insulin resistance occur, but the exact mechanism and therapeutic potential remain unclear
Solution Approach 1:
The patent uses AIM knockout mice as a feedback system to elucidate the role of AIM in NASH pathogenesis. By observing the developmental sequence of pathology in AIM-deficient mice on high-fat diet, the mechanism becomes clear: AIM suppression → adipose tissue inflammation → systemic insulin resistance → hepatic steatosis and fibrosis. This feedback approach provides both mechanistic insight and therapeutic validation.
Solution Approach 2:
The patent performs preliminary action by suppressing AIM expression before the development of NASH pathology in high-fat diet fed mice. This preliminary suppression allows the complete pathological sequence to unfold, enabling systematic analysis of each stage from fatty liver to fibrosis to cirrhosis, thereby clarifying the onset mechanism.
3Adaptability or versatility
If multiple conventional drugs (insulin sensitizers, antioxidants, liver supporting agents) are used for NASH treatment, then various symptoms can be addressed, but no established effective treatment method exists
Solution Approach 1:
The patent extracts the core therapeutic target from the complex NASH pathology by identifying AIM suppression as the central mechanism. Instead of treating multiple symptoms with various conventional drugs, the invention extracts and targets the root cause (AIM suppression), providing a unified therapeutic approach that addresses all NASH manifestations through a single mechanism.
Solution Approach 2:
The patent achieves universality by targeting AIM, which plays a central role in multiple NASH-related processes including adipose tissue inflammation, hepatic steatosis, fibrosis, and insulin resistance. A single therapeutic agent restoring AIM function can therefore address multiple aspects of NASH pathology simultaneously, providing both broad coverage and high effectiveness.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach provides a potential therapeutic agent for hepatic diseases by stabilizing or inducing AIM expression, effectively addressing the pathology of NASH and related conditions, and offers a method for diagnosing and treating fatty liver, NASH, and liver cancer by measuring AIM concentrations.
Implementation Method 1
induces degradation of accumulated neutral fats (lipolysis), and releases free fatty acid from the adipocyte
Implementation Method 2
AIM is incorporated into adipocyte by endocytosis via CD36
Implementation Method 3
The released fatty acid induces and maintains chronic inflammation in adipose tissues via stimulation of a toll-like receptor
Data Source
AI summary
The present disclosure provides a prophylactic or therapeutic agent for a hepatic disease, containing AIM or a partial peptide thereof, or a nucleic acid containing a base sequence encoding the same. The present discloses also provides a method of screening for a prophylactic or therapeutic agent for a hepatic disease, comprising using an animal obtained by loading a non-human mammal deficient in AIM expression with a high fat diet and the like.