Dissertation
Reversal of metabolic dysfunction associated steatohepatitis by fibroblast growth factor 21
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007950
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) develops as a result of dysregulation of lipid metabolism leading to excess lipid deposition in the liver. Left untreated, toxic lipid species accumulate in the liver promoting the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) with hepatocyte damage, inflammation, and fibrosis. MASLD and MASH represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction, whereas FGF21 action directly on hepatocytes is necessary and sufficient for FGF21-mediated reduction in hepatic cholesterol levels. Our data indicate that the effects of FGF21-mediated reduction of triglycerides and cholesterol are additive to resolve fibrosis in MASH. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver which suppresses hepatic de novo lipogenesis to lower hepatic triglycerides. These results provide critical insights into a promising pharmacological target to treat MASH.
Details
- Title: Subtitle
- Reversal of metabolic dysfunction associated steatohepatitis by fibroblast growth factor 21
- Creators
- Jesse P. Rose
- Contributors
- Matthew Potthoff (Advisor)Kyle Brown (Committee Member)Bhagirath Chaurasia (Committee Member)Eric Taylor (Committee Member)Ling Yang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007950
- Publisher
- University of Iowa
- Number of pages
- x, 113 pages
- Copyright
- Copyright 2025 Jesse P. Rose
- Grant note
- This data was collected with the support of a Doctoral Dissertation Research Improvement Grant (DDRIG) from the American Political Science Association and National Science Foundation.
- Language
- English
- Date submitted
- 03/06/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 93-113).
- Public Abstract (ETD)
Rates of obesity and diabetes have been steadily rising around the globe and show no signs of slowing. These diseases can overwhelm the ability of the liver to properly handle fats, causing fats to build up in the liver, which is known as metabolic dysfunction-associated steatotic liver disease (MASLD). Over time, excess fat – especially triglycerides and cholesterol – can damage the cells in the liver and cause a more severe type of liver disease called metabolic dysfunction associated steatohepatitis (MASH). When left untreated, MASH can increase the risk that patients will develop a number of health issues including heart problems, cancer, and liver failure. Even with these risks, the development of new drugs to treat MASH has been slow. One candidate therapy for MASH is a natural hormone called fibroblast growth factor 21 (FGF21). However, what FGF21 does to reverse MASH is not well understood, and the goal of this work is to provide more insight into how this important drug candidate works.
We wanted to address two questions in this study. First, what tissues in the body does FGF21 act on to heal MASH and, second, how does FGF21 change the way that the liver handles fats to reduce their accumulation. To answer these questions, we blocked the ability of FGF21 to act on specific tissues. We found that FGF21 causes the liver to stop making more triglycerides by acting on a specific type of neuron in the brain. When FGF21 acts on the brain, it causes the brain to send a signal to the liver via activation of the sympathetic nervous system, and this signal is responsible for the ability of FGF21 to lower liver fat. Additionally, we found that FGF21 acts on the liver itself to cause excretion of cholesterol from the liver. Together, the ability of FGF21 to reduce the accumulation of these two types of fats allows the liver to heal and show less signs of damage due to MASH. These results give important insights for the use of FGF21 in clinical trials for the treatment of MASH.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984831125602771
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