Role of a Novel Methyltransferase in Liver Lipid Metabolism

PROJECT SUMMARY This proposal details a career training plan for Dr. Alexander Nguyen, a gastroenterologist and hepatologist at UCLA, to become an independent academic physician-scientist in the field of liver lipid metabolism. Dr. Nguyen received his M.D./Ph.D. degrees from the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional M.D.-Ph.D. program and completed Internal Medicine residency and Gastroenterology fellowship at UCLA. During his fellowship, Dr. Nguyen initiated mentored post-doctoral research advised by Dr. Peter Tontonoz at UCLA. Dr. Tontonoz is an internationally recognized expert in the control of gene expression by lipids and the role of nuclear hormone receptors in lipid metabolism. Dr. Tontonoz has served as mentor to numerous trainees, many of whom have become successful academic investigators. Under this award, Dr. Nguyen will be supported by Dr. Tontonoz as well as his co-mentor and advisory team whose scientific expertise and mentorship will facilitate his career development. Dr. Nguyen will have the resources and expertise available to allow for the development his own independent scientific career. Dr. Nguyen will have access to courses, seminars, and core facilities through UCLA School of Medicine and the UCLA Clinical and Translational Science Institute. The described research proposal seeks to reveal the role of a novel LXR target gene, a poorly characterized methyltransferase, in liver lipid homeostasis. Preliminary studies demonstrate that this gene functions to prevent lipid accumulation in the liver when mice are fed a lipid-rich diet. Aim 1 will focus on the molecular and physiologic transcription regulation of this gene. In Aim 2, the function of this gene in the liver and physiology will be determined. In Aim 3, the hypothesis that this gene suppresses the development of steatohepatitis will be tested. These studies will uncover a novel function of this gene in the regulation of cellular and systemic lipid homeostasis and implicate pathways through which non-alcoholic fatty liver disease (NAFLD) develops. Through this award, Dr. Nguyen will develop the training necessary to become an independent physician-scientist investigator.