Researchers have identified a liver protein that regulates the daily rhythm of fat release, offering a new target for treating fatty liver disease and metabolic disorders.
The protein, known as FGF1, rises and falls in production throughout the day, acting as a timing signal that coordinates when and how much fat the liver releases into the bloodstream to fuel organs like the heart and muscles during active periods, according to a study published in Nature Communications by scientists at the Salk Institute.
This circadian control of fat secretion ensures energy balance in the body, and disrupting it by removing FGF1 in mice abolished the normal rhythm, caused fat to accumulate in the liver, and accelerated the development of fatty liver disease.
Conversely, restoring FGF1 slowed disease progression, indicating the protein’s potential as a therapeutic lever.
The rhythm persists even without external cues like light or meal times, confirming that FGF1 is driven by the liver’s internal biological clock and functions by binding to receptors on liver cells to trigger fat mobilization.
Separate research from the University of California, Los Angeles, revealed that aged and diseased livers accumulate a specific type of immune cell — dubbed “zombie” cells — that drive chronic inflammation and tissue damage despite being non-dividing and resistant to death.
These senescent macrophages, identified by a unique molecular signature of p21 and TREM2 proteins, increase from about 5% of liver immune cells in young individuals to nearly 80% with age, paralleling the rise in chronic inflammation linked to aging and fatty liver disease.
Removing these cells in mice dramatically reduced inflammation and reversed liver damage, even when the animals continued an unhealthy diet, suggesting that targeting cellular senescence could break the cycle of metabolic deterioration.
A third line of inquiry from Egyptian researchers highlighted a genetic factor, miR-93, that directly promotes fat buildup in liver cells, and showed that suppressing its activity reduces lipid accumulation.
The same study noted that vitamin B3, or niacin, supports liver function by enhancing the biochemical pathways responsible for breaking down and organizing fats, offering a nutritional angle to complement molecular interventions.
Together, the findings converge on a core insight: fatty liver disease is not merely a passive overflow of fat but a disorder of disrupted biological timing, immune aging, and genetic regulation — opening multiple avenues for treatment beyond strict dieting.
Unlike traditional approaches that focus solely on caloric restriction, these studies suggest that correcting internal timing mechanisms, clearing dysfunctional immune cells, or modulating specific gene activity could reduce liver fat independently of weight loss.
The persistence of fat-release rhythms in constant conditions implies that therapies targeting FGF1 might need to respect or reinforce natural circadian patterns to be effective.
Meanwhile, the discovery that senescent macrophages can be cleared without requiring dietary change challenges the assumption that metabolic recovery depends entirely on lifestyle modification.
Researchers caution that while results in mice are promising, translating these mechanisms to human treatments will require further validation, particularly regarding long-term safety of altering immune cell populations or circadian signaling.
No single intervention is likely to suffice; instead, combination strategies addressing circadian regulation, cellular senescence, and genetic drivers may be needed to halt or reverse fatty liver disease across different patient profiles.
What is FGF1 and why is it important for liver health?
FGF1 is a protein produced in the liver that rises and falls on a daily cycle, acting as a timing signal that regulates when and how much fat is released into the bloodstream to maintain energy balance; disrupting this rhythm leads to fat accumulation and accelerates fatty liver disease.
How do “zombie” immune cells contribute to liver damage?
These senescent macrophages, marked by p21 and TREM2 proteins, accumulate with age and in fatty livers, where they secrete inflammatory molecules that drive chronic inflammation and tissue injury, even in the absence of weight loss or dietary improvement.
Can vitamin B3 or targeting miR-93 treat fatty liver disease?
Studies show that suppressing the miR-93 gene reduces fat buildup in liver cells, and vitamin B3 supports fat metabolism pathways, but neither has been proven as a standalone treatment in humans and would require further clinical testing.