Dr. Wagner Receives Thrasher Research Fund Grant to Study How Liver Fat Affects Liver Drug Transport and Cholesterol Regulation

Jonathan Wagner, DO, Clinical Pharmacology and Toxicology and Pediatric Cardiology, was recently awarded a three-year, $383,281 E.W. “Al” Thrasher Award from the Thrasher Research Fund.

Dr. Wagner’s study, Effects of Pediatric Liver Adiposity on Statin Disposition and Response, aims to determine how liver fat affects hepatocellular drug transport as well as pediatric statin response.

With childhood obesity reaching epidemic proportions, an increasing number of children in the U.S. require chronic pharmacotherapy to reduce prematurely acquiring cardiovascular (CV) risk factors, including hypercholesterolemia (HC). As with adults, HMG-CoA reductase inhibitors (statins) are the backbone of HC treatment when lifestyle modifications fail. Despite the overall success of statin therapy, risks of toxicity and treatment failures may occur, which may be related to the varying of an individual’s circulating statin plasma concentrations and an individual’s response to a statin.

“Recently, I confirmed that genetic differences (SLCO1B1) in the protein transporters responsible for movement of statins across cell membranes into the liver is a significant source of increased circulating statin plasma concentrations in pediatric patients (Wagner et al, Clin Pharmcol Ther, 2019). However, genetic factors alone do not account for all the observed variability. Unusually high plasma concentrations were observed in obese children, independent of genotype, suggesting that obesity-related factors may contribute to diminished hepatic drug uptake and higher peripheral tissue exposure in children,” Dr. Wagner said. “Such excessive statin plasma concentrations over a sustained period of time in the developing child may result in significant adverse events, including compromised skeletal muscle function or neurologic maturation (Wagner et al, J Pediatr Pharmacol Ther, 2016).”

Dr. Wagner explains that it’s pivotal to understand the physiologic factors that contribute to the altered drug processing and response for obese children. One such physiologic factor is liver fat (adiposity), which affects a significant number of obese children and adults. There remains a critical information gap in how liver fat affects liver cell processes, such as liver drug transport (e.g. drug disposition) and cholesterol regulation in the liver (e.g. drug response). Until we learn more about this, there will continue to be a risk of drug toxicity or inadequate treatment of obesity-related comorbidities and subsequent persistence of early cardiovascular events in young adults Dr. Wagner said.

Co-investigators on the study include Valentina Shakhnovich, MD, Gastroenterology, Sherwin Chan, MD, PhD, Radiology, and Vincent Staggs, PhD, Health Services and Outcomes Research.