Stylized liver with glowing pathways, symbolizing Them2 enzyme directing fat flow.

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

Reese Marlowe monogram
Reese Marlowe in Health & Wellness November 2026 • 3 min read.

"Discover how the Them2 enzyme directs fat, offering potential new therapies for NAFLD and related conditions."


Non-alcoholic fatty liver disease (NAFLD) is a growing health concern, affecting millions worldwide. It occurs when excessive fat accumulates in the liver, leading to inflammation and potential liver damage. NAFLD is often linked to obesity, diabetes, and high cholesterol, making it a significant risk factor for cardiovascular disease and other serious conditions.

The liver's delicate balance between fat storage, breakdown, and export is crucial for overall health. When this balance is disrupted, fat accumulates, leading to NAFLD. Understanding the mechanisms that regulate this balance is essential for developing effective treatments.

Exciting new research has uncovered a key player in liver fat metabolism: an enzyme called Them2. Scientists have discovered that Them2 plays a critical role in directing fatty acids within the liver, influencing whether they are stored, burned for energy, or exported out of the liver. This discovery opens up new possibilities for treating NAFLD and related metabolic disorders.

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From Fatty Liver to NAFLD

Descriptions of fatty liver date back to the nineteenth century. Understanding of non-alcoholic fatty liver disease (NAFLD) developed through work in the twentieth and twenty-first centuries. The histopathological history of adult and childhood NAFLD includes Ludwig’s seminal studies in 1980.

Them2: The Liver's Fat Traffic Controller

Stylized liver with glowing pathways, symbolizing Them2 enzyme directing fat flow.

Them2, short for thioesterase superfamily member 2, is an enzyme that acts like a traffic controller for fatty acids within the liver. It helps decide where these fats should go, influencing critical processes such as:

Scientists at Weill Cornell Medical College and Emory University have made significant strides in understanding Them2's functions. Their research, published in a leading hepatology journal, demonstrates that Them2 promotes the synthesis of triglycerides, a type of fat that's then packaged into very low-density lipoproteins (VLDL) and shipped out of the liver.

  • Fatty Acid Oxidation: Breaking down fats for energy.
  • Triglyceride Synthesis: Creating fat molecules for storage or export.
  • VLDL Secretion: Packaging and shipping fats out of the liver.
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THEM2 and Liver Fat

In a study of high-fat-diet-fed mice, S-Them2−/− animals were protected against hepatic steatosis. This protection was not observed in L-Them2−/−6 or C-Them2−/− mice. Evidence came from histopathology and hepatic triglyceride concentrations.

Limits of the Evidence

A study reported that, after excluding patients taking lipid-lowering therapies, its small sample could not identify a correlation between liver THEM2 expression and plasma triglyceride concentrations. This finding limits how confidently THEM2 expression can be linked to circulating triglyceride levels in that sample. It also shows that experimental findings do not automatically establish the same relationship in patients.

To investigate Them2's role, the researchers created mice with a specific deletion of the Them2 gene in their livers (L-Them2). These mice provided valuable insights into how Them2 impacts liver fat metabolism. What they found was quite remarkable.

The Future of Fatty Liver Treatment

The discovery of Them2's role in liver fat metabolism offers a promising new avenue for treating NAFLD and related conditions. By targeting Them2, researchers hope to develop therapies that can restore the liver's fat balance, reduce inflammation, and improve overall metabolic health. While further research is needed, this breakthrough represents a significant step forward in the fight against fatty liver disease.

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Clinical Challenges

Expert commentary describes NAFLD as one of the leading causes of chronic liver disease worldwide. In the Middle East, its prevalence is reported as 32%, similar to the worldwide level cited by the source. Clinicians in the region face challenges in diagnosis and treatment, and the source reports that no national or regional guidelines address current concerns.

A Growing Global Burden

NAFLD has rapidly become the most common liver disease globally. It is currently estimated to affect 38% of the global population. Although only a minority of patients progress to cirrhosis or hepatocellular carcinoma, the size of the affected population means that the total number at risk of severe outcomes is increasing.

Beyond the Liver

NAFLD has emerged as a global epidemic, with a worldwide prevalence of approximately 25%. Common comorbidities include obesity, metabolic syndrome, and type 2 diabetes. These associated conditions illustrate why the disease affects patients beyond liver fat alone.

Human triglyceride sources alongside Them2 findings in mice

  • approximately 60 % of hepatic triglyceridesIn human subjects, plasma non-esterified fatty acids account for approximately 60% of hepatic triglycerides. This is a source estimate, not a measure of Them2’s effect in people.[1]

What the mouse findings say about Them2

In mice, liver-specific Them2 deletion was associated with lower plasma triglyceride and apolipoprotein B100 concentrations, even though it did not protect against hepatic steatosis. The findings distinguish changes in blood lipid measures from changes in liver fat.[2]

How Them2 fits into liver fat handling

Estimates of NAFLD prevalence span a wide range, so a single prevalence figure does not capture the variation across estimates.[1]

Them2 is described as a long-chain fatty acyl-CoA thioesterase that interacts with PC-TP and is linked to regulation of liver lipid and glucose metabolism and suppression of insulin signaling. The excerpt does not specify how these relationships connect to the separate mouse findings on blood lipids and steatosis.[3]

What remains unclear about Them2 and people

  • How do Them2’s interaction with PC-TP and its links to insulin signaling relate to the distinct blood-lipid and liver-fat outcomes reported in mice?[2] [3]

Sources

  1. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease (pmc.ncbi.nlm.nih.gov)
  2. Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis. (pubmed.ncbi.nlm.nih.gov)
  3. Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance (pmc.ncbi.nlm.nih.gov)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

Everything You Need To Know

1

What exactly is non-alcoholic fatty liver disease (NAFLD)?

Non-alcoholic fatty liver disease, or NAFLD, is a condition where too much fat builds up in the liver. This can lead to inflammation and damage. It's often associated with other health problems like obesity, diabetes, and high cholesterol, increasing the risk of heart disease and other serious conditions. Understanding and addressing NAFLD is vital for maintaining overall health.

2

What does the Them2 enzyme actually do in the liver?

The Them2 enzyme acts as a regulator of fat traffic within the liver. It influences whether fatty acids are burned for energy through fatty acid oxidation, stored as triglycerides, or exported out of the liver as very low-density lipoproteins (VLDL). This function is crucial for maintaining a healthy balance of fat in the liver.

3

What are triglycerides, and how are they related to the Them2 enzyme?

Triglycerides are a type of fat molecule created in the liver and elsewhere. The Them2 enzyme promotes the synthesis of triglycerides. These triglycerides are then packaged into very low-density lipoproteins (VLDL) and shipped out of the liver to other parts of the body. This process is essential for distributing energy and fats throughout the body.

4

How did the researchers study the Them2 enzyme to understand its function?

Scientists investigated the role of Them2 by creating mice with a specific deletion of the Them2 gene in their livers, called L-Them2. Studying these mice allowed researchers to observe how the absence of Them2 impacts liver fat metabolism. By comparing these mice to normal mice, they could determine the specific functions of the Them2 enzyme.

5

How might the Them2 enzyme be used to treat fatty liver disease?

Targeting the Them2 enzyme offers a potential new approach for treating NAFLD and improving liver health. By developing therapies that can modulate the activity of Them2, it may be possible to restore the liver's fat balance, reduce inflammation, and improve overall metabolic health. This could lead to new treatments for NAFLD and related metabolic disorders.

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