City of Hope scientists study rare disorder to uncover mechanism and hormone regulation underlying fatty liver disease and sweet aversion

LOS ANGELES — Scientists at City of Hope^®, one of the largest and most advanced cancer research and treatment organizations in the U.S. and a leading research center for diabetes and other life-threatening illnesses, have unraveled how citrin deficiency (CD), a rare genetic disorder that prevents the liver from converting food into energy efficiently, can trigger fat buildup in the liver — even in lean individuals.

Their landmark study, published in Nature Metabolism, also reveals how the liver turns on a hormone that reduces cravings for sweets and alcohol. The findings could lead to new therapies for a variety of health conditions, including fatty liver disease or MASLD (metabolic dysfunction-associated steatotic liver disease), which afflicts more than 1 billion people worldwide and increases the risk for developing type 2 diabetes and liver cancer.

The study’s lead author, Charles Brenner, Ph.D., City of Hope’s Alfred E. Mann Family Foundation Chair in Diabetes and Cancer Metabolism, observed that fatty liver disease is most common in people with obesity, yet hundreds of millions of lean people unknowingly also have this condition that programs the liver to store fat rather than burn energy.

An internationally recognized biochemist, Dr. Brenner has spent decades discovering metabolic pathways and determining how disturbances in metabolism shape health and disease. Dr. Brenner was struck by two unusual facts: (1) nearly all CD patients are lean, yet they have MASLD (2) people with CD share an aversion to sweets.

Knowing that the liver increases levels of the FGF21 hormone in multiple conditions of metabolic stress and that high doses of FGF21 cause an aversion to sweets and alcohol, Dr. Brenner hypothesized that specific stress in CD drives fatty buildup in the liver and the production of FGF21.

“Much like how the study of rare, inherited cases of breast cancer in men led to pinpointing key genes that drive common cases of breast cancer in women, we utilized CD as a model to understand why the liver would generate and not burn fat in the lean state,” Dr. Brenner said. “We found that the key is the accumulation of a small molecule called G3P that activates ChREBP, a protein that turns on fat synthesis genes.”

The work was surprising because G3P had not previously been identified as the activator of ChREBP, and the conditions that induce FGF21, which include both ketogenic diet (the absence of carbohydrates) and consuming simple carbohydrates, had eluded understanding.

Based on the research, the G3P mechanism has the potential to explain the liver’s logic of fat synthesis while also explaining how G3P functions as a stress signal to turn on FGF21.

The findings suggest novel therapeutic approaches to resolve MASLD. When G3P-ChREBP turns on fat synthesis, it also turns off fat burning in a way that could be targeted by drugs. In addition, G3P-based drugs could be prescribed by physicians to get the effects of FGF21, namely curb the appetite for sweets while also turning on fat-burning pathways.

Ongoing research will be key in exploring these avenues for treatment, offering hope for people with CD, lean individuals with fatty liver disease, and others for whom FGF21-based therapeutics may aid weight loss and/or promote a healthier diet and lifestyle.

“Our chief goal is to transform our understanding of metabolic dysfunction into tangible benefits for people facing these interconnected diseases,” Dr. Brenner said. “By helping uncover new ways to treat root causes, this study brings us one step closer to achieving that objective.”

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The preclinical study titled, “Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency,” was supported by the Alfred E. Mann Family Foundation, the Arthur Riggs Diabetes and Metabolism Research Institute, the National Institutes of Health (R01DK012170, R01DK100425, R01DK118011, R01DK136671, R01HL147545 and P30CA33572), the American Diabetes Association (11-22-JDFPM-06) and the Burroughs Wellcome Fund.

Work in Dr. Brenner’s laboratory was performed by Vinod Tiwari, Olivia Sun and Edwin D.J. Lopez Gonzalez with the support of Min-Hsuan Chen and Xiwei Wu. Dr. Brenner was joined by Massachusetts General Hospital hepatologist Russell P. Goodman with Byungchang Jin and Andrew Zhang. Hardik Shah, Mark D. Herman and Cassandra N. Spracklen participated from The University of Chicago, Baylor College of Medicine and University of Massachusetts, respectively.

About City of Hope 
City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the United States, and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked Top 5 “Best Hospital” in the nation for cancer care by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope^TM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn.