Illustration Credit: Credit: Young Do Koo
Scientific Frontline: Extended "At a Glance" Summary: ULK1 Enzyme and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
The Core Concept: ULK1 is a kinase enzyme operating within the liver that actively protects against metabolic dysfunction-associated steatotic liver disease (MASLD), an obesity-linked condition that drives progressive liver failure.
Key Distinction/Mechanism: While previously known for its role in cellular recycling (autophagy), ULK1 protects the liver through a completely independent mechanism. It prevents excessive fat synthesis by phosphorylating a specific protein called NCOA3. When ULK1 is deficient, uninhibited NCOA3 accelerates the creation of fatty acids and triglycerides, directly leading to insulin resistance and tissue inflammation.
Major Frameworks/Components:
- ULK1 (Unc-51 Like Autophagy Activating Kinase 1): A kinase enzyme that regulates cellular processes by attaching phosphate groups (phosphorylation) to target proteins to switch their activity on or off.
- NCOA3: A regulatory protein functioning within a nuclear multi-protein complex (NCOA3-CBP-CREB) that drives hepatic fat synthesis when not repressed by ULK1.
- MASLD to MASH Progression: The pathophysiological pipeline where benign fat accumulation advances to metabolic dysfunction-associated steatohepatitis (MASH), causing cirrhosis and severe tissue scarring.
- Small Molecule Inhibition (SI-2): A chemical inhibitor utilized in the study to successfully suppress NCOA3, which normalized liver fat synthesis and reduced inflammation even in models lacking the ULK1 gene.
Branch of Science: Molecular Endocrinology, Hepatology, Cellular Biology, and Metabolic Physiology.
Future Application: This discovery establishes the ULK1-NCOA3 interaction as a primary target for novel pharmacological interventions. Future drugs utilizing targeted small molecule inhibitors could therapeutically mimic ULK1's protective effects, directly halting or reversing MASLD progression in human patients.
Why It Matters: MASLD incidence is rapidly increasing worldwide, yet there are currently few condition-specific therapies available. Unlocking this direct, autophagy-independent mechanism provides a targeted therapeutic avenue to treat liver inflammation, glucose intolerance, and progressive liver failure without having to rely solely on broader, systemic weight-loss medications like GLP-1 agonists.
In a mouse and human study, a UCLA-led team has found how an enzyme called ULK1, working in the liver, protects against metabolic dysfunction associated fatty liver disease (MASLD), an obesity-linked liver condition that is a leading cause of liver failure requiring a transplant.
The findings of the study, published in the peer-reviewed Journal of Clinical Investigation, unlock previously unrecognized insights about ULK1’s function that open a path to new therapies for MASLD. Dr. E. Dale Abel, chair of the UCLA Department of Medicine, and Young Do Koo, assistant professor in the division of endocrinology, diabetes and metabolism at the David Geffen School of Medicine at UCLA, led the research team.
MASLD is a highly variable syndrome that in some people can progress to metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of fatty liver disease that can lead to tissue scarring, cirrhosis, liver failure and liver cancer. MASLD is closely linked to insulin resistance and obesity-associated chronic disease, and its incidence is rapidly rising worldwide. However, the mechanisms that lead to its development and progression remain poorly understood.
Thus, while treatments like GLP-1 agonists that mitigate some of the features of MASLD may act in part by reducing obesity, there are few therapies specific to the condition itself. However, some evidence suggests that autophagy — a naturally-induced state in which the body clears out, recycles or repairs old or dysfunctional cells in response to nutrient deprivation or fasting — can protect against MASLD. There is therefore much interest in leveraging autophagy as a therapeutic strategy.
The study by Abel’s team adds nuance to this concept and reveals that ULK1 could be an important therapeutic target. ULK1 has been well-studied for its role in autophagy, but it was previously unclear whether autophagy alone could be responsible for any role that ULK1 could have in protection against MASLD. To establish a potential link, Dr. Abel’s team first analyzed data on the expression of ULK1 in liver samples from people with and without MASLD and in mice that were fed a high-fat diet (HFD). ULK1 expression was lower in people with the disease compared to healthy individuals, indicating a correlation between MASLD and ULK1 deficiency.
Next, the scientists developed a mouse model lacking the gene that encodes for ULK1 specifically in liver cells — in other words, a liver- specific ULK1 “knockout” model. A series of experiments with the ULK1 knockout mouse model demonstrated that it plays a direct, independent role in MASLD development: Mice without the protein in their livers had higher levels of liver triglycerides and progressed to MASH when fed a HFD. They also more readily developed insulin resistance and glucose intolerance. Even in animals that had not yet become obese or developed insulin resistance, the absence of the gene sped up fatty acid and triglyceride creation in the liver.
Unexpectedly autophagy was not impaired in the liver even in the absence of ULK1, suggesting that the mechanism by which ULK1 protects from the development of MASLD are independent from its role in autophagy. ULK1 is a specific type of enzyme called a kinase, which exerts its activity on cellular processes via phosphorylation, which means attaching a phosphate group to a protein in order to switch its activity on or off. In this case, the researchers hypothesized that ULK1 might be influencing fat synthesis in the liver by phosphorylating proteins with direct roles in that process.
Their experiments pointed to a protein called NCOA3, which regulates fat synthesis through its interactions within a multi-protein complex in the nucleus called NCOA3-CBP-CREB. The team found that phosphorylation of NCOA3 by ULK1 prevents fat synthesis in the liver, and that knocking out the genes for both ULK1 and NCOA3 in the same mouse, prevented the MASLD and insulin resistance observed in the mice in which only ULK1 was knocked out. This NCOA3-dependent effect was validated in experiments where NCOA3 was inhibited with a small molecule, SI-2. Treatment of ULK1 KO mice with SI-2 normalized fat synthesis in the livers of these animals despite the fact that they did not possess the ULK1 gene, demonstrating that its interaction with NCOA3 was the culprit behind MASLD development. NCOA3 inhibition with SI-2 also reduced inflammation in livers of ULK1 knockout mice, suggesting that it works at multiple levels against the mechanisms that lead to MASLD. Changes in these inflammatory pathways were also noted in human samples from MASLD patients who had reduced levels of ULK1.
There is still much more to learn about how ULK1 comes to be repressed in MASLD in the first place. Future studies by the same team will seek to elucidate these mechanisms. In the meantime, they will continue to explore the development of drugs that target the interaction between ULK1 and NCOA3, with the aim of ultimately testing them in humans.
Funding: The study was funded by the American Heart Association Strategically Focused Research Network.
Published in journal: Journal of Clinical Investigation
Authors: Young Do Koo, Romilia Tatiana Castillo, Asha Sukumaran Nair, Michael Garneau, Chad Gochee, Zachary V. Campbell, Tashya Shreyas Vakil, Jua Ha, Alex Marti, Jamie Soto, Debajyoti Das, Nuria Martinez-Lopez, Shipra Sharma, Yennifer Delgado, Callie Phung, Immy A. Ashley, Edmund D. Kapelczak, Rashel Jacobo, Eric T. Weatherford, Dao-Fu Dai, Jihane N. Benhammou, Andrea G. Marshall, Antentor Hinton Jr, Ling Yang, Renata O. Pereira, Tara TeSlaa, Mehdi Bouhaddou, Rajat Singh, and E. Dale Abel
Source/Credit: University of California, Los Angeles / Health | Rosa M. Guerrero
Reference Number: mbio041826_01