Development of Non-Invasive Imaging Probes for Assessing Altered Mitochondrial Metabolism of Non-Alcoholic Fatty Liver Disease
Abstract
The global obesity crisis is marked by a considerable number of healthcare complications, and chief among them are type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). NAFLD affects ~30% of the general population, the majority of overweight individuals, and roughly 80% of those with T2D. Despite rigorous fitness requirements, military personnel experience unique stressors that predispose them to metabolic disease. It is estimated that 54% of men and 34% of women on active duty are overweight, and 12% are obese. NAFLD in the active military has increased by 1,200% over the past 17 years, and Veterans are at increased risk for developing NAFLD compared to the general population. There are several common metabolic drivers shared by T2D and NAFLD, including the accumulation of lipid in normally lean tissue (i.e., liver and muscle), and alterations in mitochondrial metabolism. Changes in the latter mark an important swing in metabolic health, yet there are no non-invasive clinical exams to detect it. This project will develop new technology that can be used by physicians to diagnose and monitor changes in mitochondrial metabolism. The proposed project addresses diabetes and mitochondrial disease of the FY21 PRMRP Topic Areas. In part, this study addresses the following FY21 Areas of Encouragement: • Diabetes: Understanding factors/mechanisms responsible for adverse metabolic effects (insulin resistance, beta cell dysfunction, dyslipidemia, non-alcoholic fatty liver disease) of obesity and why some people with obesity are protected from the adverse metabolic effects of excess adiposity. • Mitochondrial Disease: Identification and testing of non-invasive techniques and biomarkers to monitor mitochondrial function, aid in clinical diagnosis, and/or evaluate therapeutic efficacy. • Mitochondrial Disease: Research to better understand the progression of mitochondrial diseases. NAFLD is a spectrum of liver conditions and is generally divided into two categories: benign fatty liver and non-alcoholic steatohepatitis (NASH). For many patients, the benign clinical course can linger for decades. However, approximately 10%-20% will go on to develop NASH, a condition characterized by a combination of fatty liver, inflammation, and fibrosis. NASH greatly increases the risk for progression to cirrhosis, end-stage liver disease and, in some patients, hepatocellular carcinoma (HCC). It has been projected that in the next 10 years, half a million Veterans will progress from NAFLD to NASH and >100,000 will develop cirrhosis. NASH-related liver damage is quickly outpacing hepatitis C as the most common cause for liver transplant. While several methods are available to detect fatty liver, the definitive diagnosis of NASH relies on liver biopsy, which cannot test the entire liver and has serious complications that generally prevent repetitive measurements. Despite extensive investigation, non-invasive tools for staging liver disease are yet to be established. Differentiating simple steatosis from NASH represents a particularly critical clinical objective for several reasons. First, the management of these two disease states are significantly different, thus driving the urgent need for improved non-invasive diagnosis and staging. Second, despite a liver transplant list populated by subjects with NASH-related disease, liver donors are frequently rejected even if they are suspected of having mild fatty liver. A non-invasive imaging approach would better guide these decisions in certain donor populations. Finally, there is a lack of therapeutic interventions and treatment guidelines for NASH, primarily because the pathway of pathological progression from benign fatty liver to NASH and cirrhosis remains unclear. In some cases, it is suspected that patients may progress immediately from NAFLD to cirrhosis with very little warning. This gap remains poorly understood because the natural history of the disease cannot be studied by
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210485
Entities
People
- Jae Mo Park
Organizations
- United States Army
- University of Texas Southwestern Medical Center