Surreal image of a liver with glowing metabolic pathways, highlighting the Them2 enzyme.

Unlocking the Liver's Secret: How This Enzyme Could Revolutionize Fatty Liver Disease Treatment

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Samir D’Costa in Health & Wellness December 2025 • 4 min read.

"Discover how Them2, a key enzyme in liver metabolism, could be the next big target for treating NAFLD and improving overall metabolic health."


Non-alcoholic fatty liver disease (NAFLD) is a growing health concern, characterized by the accumulation of triglycerides within the liver. This occurs when the rate of fat accumulation, through uptake from the plasma and synthesis within the liver, exceeds the rate at which it is broken down or secreted. Understanding the mechanisms that regulate this balance is crucial for developing effective treatments.

A key player in this process is Thioesterase superfamily member 2, or Them2, an enzyme that helps to regulate how fatty acids are used in the body. Them2 is found in high concentrations in the liver and other tissues that require a lot of energy, influencing the breakdown of fatty acyl-CoAs into free fatty acids and CoASH. This process is essential for maintaining metabolic health, and imbalances can contribute to diseases like NAFLD.

Recent studies have delved into the specific role of Them2 in the liver. By creating models with and without Them2, researchers have been able to pinpoint how this enzyme affects fat metabolism, VLDL secretion, and overall liver health. These findings suggest that Them2 could be a crucial target for managing NAFLD and improving metabolic function.

Them2: A Central Regulator of Liver Fat Metabolism

Surreal image of a liver with glowing metabolic pathways, highlighting the Them2 enzyme.

Researchers have discovered that Them2 plays a vital role in directing how fatty acids are processed in the liver. Specifically, Them2 appears to channel fatty acids towards the synthesis of triglycerides, which are then incorporated into very low-density lipoprotein (VLDL) particles for secretion. This process helps to manage fat levels in the liver and prevent the buildup that leads to NAFLD.

Studies using models with liver-specific deletions of Them2 (L-Them2) have shown significant impacts on fat metabolism. These models experienced marked decreases in plasma triglyceride and apolipoprotein B100 concentrations. These changes highlight Them2's importance in VLDL secretion, indicating that it helps the liver export fats effectively.

  • Reduced VLDL Secretion: L-Them2 models exhibited lower rates of VLDL secretion, suggesting that Them2 facilitates the movement of fats out of the liver.
  • Increased Fatty Acid Oxidation: In the absence of Them2, the liver compensated by increasing the rate at which it burned fatty acids, preventing fat buildup.
  • Decreased Lipogenesis: The models also showed a decrease in the production of new fats, further aiding in the prevention of hepatic steatosis.
These findings suggest that Them2 is crucial for maintaining a healthy balance of fat metabolism in the liver. It ensures that fats are either used for energy or exported out of the liver, preventing the dangerous accumulation that characterizes NAFLD.

Implications for Future Treatments

Given the significant role of Them2 in liver fat metabolism, it represents a promising target for the development of new treatments for NAFLD and related metabolic disorders. By modulating the activity of Them2, researchers hope to find ways to restore healthy fat metabolism, reduce liver fat accumulation, and improve overall metabolic health. As research continues, Them2 may well become a cornerstone in the fight against fatty liver disease, offering new hope for those affected by this widespread condition.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

Everything You Need To Know

1

What is Them2 and why is it important?

Them2, or Thioesterase superfamily member 2, is an enzyme primarily found in the liver and other high-energy-demanding tissues. It plays a crucial role in regulating how fatty acids are utilized in the body. Specifically, Them2 influences the breakdown of fatty acyl-CoAs into free fatty acids and CoASH. This process is essential for maintaining metabolic health, and imbalances in Them2's function can contribute to diseases like NAFLD.

2

How does Them2 affect fat metabolism in the liver?

Them2 directs fatty acids towards the synthesis of triglycerides, which are then incorporated into very low-density lipoprotein (VLDL) particles for secretion. This process helps to manage fat levels in the liver. Studies using models with liver-specific deletions of Them2 (L-Them2) showed decreased VLDL secretion, increased fatty acid oxidation, and decreased lipogenesis, highlighting Them2's importance in exporting fats and preventing fat buildup that leads to NAFLD.

3

What is NAFLD and how does Them2 relate to it?

Non-alcoholic fatty liver disease (NAFLD) is a condition characterized by the accumulation of triglycerides within the liver. Them2 is crucial in preventing this buildup. It ensures that fats are either used for energy or exported out of the liver. By facilitating VLDL secretion, Them2 helps manage fat levels, and its dysfunction can contribute to the development and progression of NAFLD.

4

What were the key findings in the L-Them2 models, and what do they indicate?

L-Them2 models, which lacked Them2 in the liver, showed several key changes. These included reduced VLDL secretion, indicating that Them2 facilitates the movement of fats out of the liver; increased fatty acid oxidation, where the liver compensated by burning more fatty acids, preventing fat buildup; and decreased lipogenesis, reducing the production of new fats. These findings collectively demonstrate that Them2 is vital for maintaining healthy fat metabolism and preventing the dangerous fat accumulation characteristic of NAFLD.

5

How might Them2 be used in future treatments for NAFLD?

Given the significant role of Them2 in liver fat metabolism, it represents a promising target for the development of new treatments for NAFLD. Researchers hope to modulate the activity of Them2 to restore healthy fat metabolism, reduce liver fat accumulation, and improve overall metabolic health. By targeting Them2, therapies could potentially restore the balance of fat processing within the liver, offering new strategies in the fight against fatty liver disease and related metabolic disorders.

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