A team led by Gerald I. Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, has uncovered a new process that potentially delays the development of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD).
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. Recent studies have found that a common variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. In a study published in the Proceedings of the National Academy of Sciences (Jan 2023) Shulman and his team investigated the effects of this variant in the human liver and in Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach.
In this study they demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, they found that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13-induced protection against liver fibrosis. From these results Shulman states: “Taken together these results suggest that inhibition of dihydropyrimidine dehydrogenase may be a novel therapeutic target to prevent the progression of NAFLD to liver fibrosis”.
One particular area of future interest involves assessing the role of this pyrimidine catabolism pathway in stimulating a fibrotic response in stellate cells within the liver. Further studies assessing how pathways involving pyrimidine catabolism affect these specific cells within the liver directly or indirectly are eagerly awaited.
Along with Shulman, authors include Panu K. Luukkonen; Ikki Sakuma; Rafael C. Gaspar; Meghan Mooring; Ali Nasiri; Mario Kahn; Xian-Man Zhang; Dongyan Zhang; Henna Sammalkorpi; Anne K. Penttilä; Marju Orho-Melander; Johanna Arola; Anne Juuti; Xuchen Zhang; Dean Yimlamai, MD/PhD; Hannele Yki-Järvinen; and Kitt Falk Petersen, MD.
Yale’s Section of Endocrinology & Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge; applying new information to patient care; and training the next generation of physicians and scientists to become leaders in the field. To learn more about their work, visit Endocrinology & Metabolism