Abstract
In the United States non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. It occurs in every age group, but predominantly in people with risk factors such as obesity and type 2 diabetes. NAFLD is marked by fat accumulation in the liver leading to liver inflammation, which may lead to scarring and irreversible damage progressing to cirrhosis and liver failure. In animal models, genetic ablation of the protein G0S2 leads to alleviation of liver damage and insulin resistance in high fat diets. The research presented in this paper aims to aid in rational based drug design for the treatment of NAFLD by providing a pathway for a solution state NMR structure of G0S2. Here we describe the expression of G0S2 in an E. coli system from two different constructs, both of which are confirmed to be functionally active based on the ability to inhibit the activity of Adipose Triglyceride Lipase. In one of the constructs, preliminary NMR spectroscopy measurements show dominant alpha-helical characteristics as well as resonance assignments on the N-terminus of G0S2, allowing for further NMR work with this protein. Additionally, the characterization of G0S2 oligomers are outlined for both constructs, suggesting that G0S2 may defensively exist in a multimeric state to protect and potentially stabilize the small 104 amino acid protein within the cell. This information presented on the structure of G0S2 will further guide future development in the therapy for NAFLD.
Highlights
Liver steatosis develops when these fatty acids become concentrated in liver tissue
Steatosis of liver tissue is associated with Non-Alcoholic Fatty Liver Disease (NAFLD) that is characterized by fat accumulation in the liver leading to liver inflammation, which may cause scarring and irreversible damage progressing to cirrhosis and liver failure
Two constructs were used for the structural studies in this paper: a maltose binding protein (MBP) construct (Fig 2A) and a SUMO-G0S2 construct (Fig 2B)
Summary
Liver steatosis develops when these fatty acids become concentrated in liver tissue. Steatosis damages cells, resulting in large nutritional deficiencies, cell death, and permanent scarring of tissue by storage of triglycerides inside the cell [1]. Steatosis of liver tissue is associated with Non-Alcoholic Fatty Liver Disease (NAFLD) that is characterized by fat accumulation in the liver leading to liver inflammation, which may cause scarring and irreversible damage progressing to cirrhosis and liver failure. In the United States, NAFLD is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people [2, 3]. It occurs in every age group, but especially in people with risk factors such as obesity and type 2 diabetes. There are no drugs that have passed FDA standards in treatment of NAFLD, and the breaking down of triglycerides through lipolysis remains a primary target for drug development [7]
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