Location: Children's Nutrition Research Center
2021 Annual Report
Objectives
Objective 1: Use animal and cell culture models to investigate the interaction of various phospholipid species with the LRH-1 nuclear receptor, and determine the potential metabolic benefits to insulin resistance in obesity.
Subobjective 1A: Combine biochemical and functional studies to identify specific endogenous PC species as LRH-1 agonist ligands.
Subobjective 1B: Develop functional tests of the activity of endogenous LRH-1 agonists in mouse models of insulin resistance and diabetes.
Objective 2: Use transgenic mice with liver specific knockout of the liver receptor homolog LRH-1 nuclear receptor to critically test its role as the potential mediator of the metabolic benefits of phosphatidylcholine agonist ligands in obesity. Confirmation of possible benefits will be through clinical trials in obese human subjects with insulin resistance.
Subobjective 2A: Test the ability of both endogenous LRH-1 agonists and laurate supplementation to improve metabolic status in mouse models of obesity and insulin resistance. These studies will use both genetic loss of LRH-1 function in the liver and replacement of mouse LRH-1 with human LRH-1 to confirm the LRH-1 dependence of the beneficial effects of phospholipid or laurate supplementation.
Subobjective 2B: Define optimal strategies for anti-diabetic effects of LRH-1 activation in mouse models and validate a therapeutic strategy appropriate for use in human studies.
Objective 3: No longer pursued due to investigator departure (LF)
Objective 4: No longer pursued due to investigator departure (LF)
Approach
Obesity-related non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level world-wide. NAFLD is closely associated with obesity-related comorbidities, such as type 2 diabetes, and has also recently emerged as a direct driver of hepatocellular carcinoma (HCC). However, the mechanisms that induce NAFLD and link it to pathologic outcomes are poorly understood, and there are no approved medical treatments for NAFLD. We have reported that activation of the nuclear receptor LRH-1 by an exogenous non-natural phosphatidylcholine (PC) species, dilauroyl PC (DLPC), reduces liver fat accumulation and NAFLD-associated insulin resistance, and also that chronic circadian disruption induces leptin resistance, NAFLD, and HCC independent of other risk factors. We will study the role of endogenous PCs in the prevention and treatment of NAFLD and insulin resistance, and test the hypothesis that beneficial effects of these natural PCs are due to LRH-1 activation. Our studies will lead to conceptual advances in our understanding of obesity-related NAFLD, type 2 diabetes, and HCC, and the development of novel therapeutic strategies for the prevention and treatment of NAFLD and its associated diseases.
Progress Report
No progress was made as the research scientist conducting this work resigned and is no longer involved with the Children's Nutrition Research Center.
Accomplishments
