Mechanism of ketogenic diet-induced hypercholesterolemia

/ABSTRACT The purpose of this career development award is to prepare Max Petersen, M.D., Ph.D., for a career in mechanistic clinical investigation of ketone and lipid metabolism in cardiometabolic health and disease. The three central objectives of the career development plan are: i) to acquire the experience and training needed to become an independent clinical investigator; ii) to develop specific expertise in clinical investigation of the physiology of ketosis and ketogenic diets; and iii) to develop specific expertise in lipid and lipoprotein kinetics research. The research strategy and career development plan will be carried out in the world-class clinical and basic research facilities of Washington University School of Medicine in St. Louis, MO. The objective of the research project is to conduct a clinical physiology study evaluating the mechanism of ketogenic diet-induced hypercholesterolemia (KDHC) in susceptible normal-weight adults. KDHC is a significant safety concern that limits the use and acceptance of ketogenic diet interventions in medicine. The Specific Aims will systematically test several proposed mechanisms for KDHC. In Aim 1, we will test the hypothesis that KDHC is primarily caused by an increased VLDL-ApoB production rate (primary outcome) and is associated with increased whole-body lipolysis and plasma LPL activity. In Aim 2, we will evaluate the alternative hypotheses that KDHC is caused by decreased LDL clearance, increased LDL production rate, and/or increased cholesterol synthesis. We will also evaluate the impact of endocrine factors (adipokines, thyroid hormones, insulin sensitivity) and cholesterol absorption on individual susceptibility to KDHC in this aim. These outcomes will be measured in a cohort of healthy, young, normal-weight adults (n = 24) pre- identified as KDHC Responders who experience KDHC after adopting a three-week screening KD. KDHC Responders will complete a randomized crossover trial with isotope tracer studies of lipoprotein and cholesterol kinetics after consuming an isocaloric ketogenic diet and an isocaloric control diet. The results will yield fundamental insights into the nutritional physiology of lipoprotein and cholesterol metabolism in people. The primary and secondary mentors for this project are Samuel Klein, M.D., and Victor Dávila-Román, M.D., who have a distinguished track record of mentoring physician-scientists to independence. In addition, a Scientific Mentoring Team of experts will provide specific training in: i) analytical procedures for lipoprotein kinetic studies; ii) compartmental modeling techniques; iii) determination of LPL activity; iv) advanced biostatistics; v) mass spectrometry; and vi) interaction of dietary composition with the circulating lipoprotein profile. A career development advisory committee of three senior physician-scientists who are experienced in mentoring junior faculty will supervise and aid Dr. Petersen’s development into an independent clinical investigator studying ketone and lipid metabolism in cardiometabolic health and disease. Project Number: 1K23HL179482-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Max Petersen | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $201,222 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZRG1 RCCS-U (94)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL17948201A1