Defining choline metabolism in metabolic health

About This Grant

Project Summary The impairment in choline catabolism to its methyl-donor, betaine, is strongly related to the development of metabolic-associated liver disfunction (MASLD). In order for choline to be metabolized, it must be transported into the mitochondrial matrix. However, limitations in the understanding subcellular localization of choline have limited the understanding of choline metabolism in the development of MASLD. My work has identified SLC25A48 as a mitochondrial choline carrier (MChoC, SLC25A48) which regulates choline subcellular localization and metabolism. Elucidating the regulation choline metabolism under obese conditions may reveal novel mechanisms of treating MASLD. This proposal tests the hypothesis that diet induced obesity disrupts choline contribution to the methionine cycle which regulates metabolic health. A first set of studies focuses on the regulation of choline flux in the liver. I will map the fate of choline in the livers of control and MChoC liver- specific knockout (MChoC-LKO) mice through in vivo flux analysis with stable-labeled choline coupled with LC/MS. I will also determine whether overexpression of MChoC in livers of obese mice is sufficient to rescue fatty liver disease. A second set of studies will focus on choline dependent changes in epigenetics. This set of studies will expand my technical training with support from co-mentor Dr. Evan Rosen. To address the epigenetic modifications dependent on choline metabolism we will assess chromatin architecture regulated through histone methylation and translational control through polysome profiling in MChoC-LKO mice. A third set of studies will test the regulation of obesity on the choline metabolic pathway through proximal-labeling and in vivo complex assessment. Completion of these studies will expand the scope of my work, provide foundational datasets, and establish models that will be essential toward achieving my career goal of leading and developing scientists as an independent investigator.