Scientists uncover how citrin deficiency causes liver fat buildup in lean people - Video

How can lean, healthy-looking people develop fatty liver disease? New research from the City of Hope offers a surprising answer: a small molecule in the liver that tricks it into storing fat instead of burning it. The study, published in Nature Metabolism, reveals how citrin deficiency (CD)-a rare genetic disorder that disrupts the liver’s ability to convert food into energy-can trigger fat buildup even in thin individuals. The same mechanism, researchers say, may help explain fatty liver disease (MASLD) in millions worldwide and open the door to new treatments.

Fatty liver disease is often linked to obesity, but millions of lean people also develop it unnoticed, making its root causes a mystery. To solve this puzzle, Dr. Charles Brenner, head of the Diabetes and Cancer Metabolism Program at City of Hope, studied citrin deficiency as a model. CD patients share two curious traits: they remain lean yet have fatty livers, and they instinctively avoid sweets and alcohol. Brenner’s team suspected the liver’s stress response might drive both effects.

Using molecular and metabolic models, researchers discovered that when the liver lacks citrin, levels of the molecule glycerol 3 phosphate (G3P) surge. This buildup activates ChREBP, a protein that flips on genes responsible for producing and storing fat, effectively programming the liver to accumulate rather than burn fat. At the same time, G3P acts as a stress signal that triggers higher levels of FGF21, a hormone known to suppress cravings for sugar and alcohol while promoting fat metabolism.

The dual action of G3P—fueling fat buildup but also prompting hormonal self correction-helps explain why lean people with CD develop fatty livers yet shun sweet foods. It also provides a missing link between metabolic stress, diet behavior, and liver health.

These findings point to promising therapeutic targets. Drugs that block the G3P–ChREBP pathway could reduce fat synthesis in the liver, while G3P based or FGF21 mimicking therapies might help regulate appetite and enhance fat burning. “By understanding how metabolism goes awry, we can design smarter ways to restore balance,” said Dr. Brenner.

With fatty liver disease now affecting over a billion people globally, this discovery could reframe how researchers—from metabolic biology to nutrition science—approach one of today’s fastest growing health crises.

REFERENCE: Tiwari, V., et al. (2025). Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency. Nature Metabolism. DOI: 10.1038/s42255-025-01399-3. https://www.nature.com/articles/s42255-025-01399-3