Illustration of liver metabolic pathways with Them2 enzyme highlighted.

Unlocking Liver Health: How This Enzyme Could Be The Key To Fighting Fatty Liver Disease

Mira Elwood monogram
Mira Elwood in Health & Wellness October 2026 • 4 min read.

"New research spotlights the role of Thioesterase Superfamily Member 2 (Them2) in managing liver fat and its potential as a therapeutic target for NAFLD."


Non-alcoholic fatty liver disease (NAFLD) is a growing health concern, characterized by the accumulation of triglycerides within the liver. This occurs when the balance between fatty acid accrual and elimination is disrupted, leading to a range of metabolic complications.

Recent research has shed light on the crucial role of Thioesterase Superfamily Member 2 (Them2) in regulating liver fat metabolism. Them2 is an enzyme that influences how fatty acids are processed in the liver, specifically directing them towards triglyceride synthesis.

Them2 could be a key player in addressing NAFLD. This article explores how Them2 functions, its impact on liver health, and its potential as a target for future therapies.

AI Search Multiple angles on this topic

The Growing Global Burden of Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease worldwide, with its global burden increasing steadily from 1990 through 2021. In the United States alone, approximately 4.5 million adults have been diagnosed with liver disease, and the condition contributed to over 56,000 deaths in a single year. This rising prevalence mirrors the global surge in metabolic diseases such as obesity and type 2 diabetes.

Diagnostic Gold Standards and Their Practical Challenges

The gold standard for diagnosing liver fibrosis severity remains histological assessment via liver biopsy. However, given that NAFLD affects roughly 25% of the global adult population, performing invasive biopsies on all patients is neither feasible nor safe. Biopsies are costly, invasive, and prone to sampling errors, driving the medical community toward non-invasive diagnostic alternatives despite their own limitations.

From 19th-Century Observations to Modern Understanding

The recognition of fatty liver as a clinical entity dates back to the nineteenth century, when physicians first described hepatic fat accumulation in autopsy findings. Over the following century, researchers gradually distinguished non-alcoholic forms of the disease, culminating in the formal definition of NAFLD in the late twentieth century. Today, NAFLD has become the leading indication for liver transplantation in women and the second most common in men in Western countries, yet no approved pharmacological therapies currently exist.

Them2: A Closer Look at Its Role in Liver Fat Metabolism

Illustration of liver metabolic pathways with Them2 enzyme highlighted.

Them2, or Thioesterase Superfamily Member 2, is an enzyme that catalyzes the hydrolysis of fatty acyl-CoAs into free fatty acids. It's highly expressed not only in the liver but also in other oxidative tissues. Research indicates that Them2 plays a significant role in managing how the liver processes fats, influencing overall metabolic health.

To investigate Them2's function, scientists conducted studies using mice with a liver-specific deletion of the Them2 gene (L-Them2). The results revealed that these mice, while not protected against weight gain or glucose intolerance, exhibited notable decreases in plasma triglyceride and apolipoprotein B100 concentrations.

  • Decreased VLDL Secretion: L-Them2 mice showed reduced rates of VLDL (very low-density lipoprotein) secretion, indicating that Them2 influences the liver's ability to export fats into the bloodstream.
  • Compensatory Mechanisms: The absence of hepatic steatosis in L-Them2 mice was attributed to increased rates of fatty acid oxidation and decreased de novo lipogenesis (the creation of new fat) in high-fat-fed mice.
  • Increased Them2 in Human NAFLD: Consistent with its role in VLDL secretion, levels of THEM2 were found to be elevated in the livers of obese patients with NAFLD characterized by simple steatosis.
AI Search Multiple angles on this topic

Evolving Terminology and Expanding Research Frontiers

Recent years have seen a significant shift in how the medical community classifies and研究s fatty liver disease. The condition has been reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), reflecting a move away from exclusionary and potentially stigmatizing language. Comprehensive reviews estimate that NAFLD affects approximately one-quarter of the global population, underscoring its status as a major public health priority.

Unresolved Questions and Therapeutic Gaps

Despite decades of research, the development of effective pharmacological treatments for NAFLD has been largely disappointing. Numerous clinical trials targeting various pathways in disease progression have failed to demonstrate clear, sustained benefits. The reliance on lifestyle modifications such as diet and exercise, while foundational, often proves insufficient for many patients, highlighting a persistent gap between scientific understanding and practical therapeutic solutions.

Distinctions Between Fatty Liver Disease Subtypes

While both alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease can progress to cirrhosis and liver failure, their underlying causes differ significantly. In their early stages, however, the hepatic damage from both conditions can potentially be reversed. The recent reclassification from NAFLD to MASLD also clarifies the relationship between NAFL (simple steatosis) and the more severe NASH (steatohepatitis), emphasizing that metabolic dysfunction, rather than alcohol consumption, is the defining feature.

These findings suggest that Them2 directs fatty acids towards triglyceride synthesis for incorporation into VLDL particles, playing a crucial role in managing liver fat and overall lipid metabolism.

Them2: A Promising Target for Future Therapies

The research highlights Them2 as a potential therapeutic target for managing NAFLD and related metabolic disorders. By understanding how Them2 influences liver fat metabolism, scientists may develop targeted treatments to improve liver health and combat the growing epidemic of fatty liver disease.

AI Search Multiple angles on this topic

Consensus on the Urgency of the NAFLD Crisis

The medical and scientific communities broadly agree that NAFLD represents one of the most pressing hepatological challenges of the 21st century. Experts consistently emphasize the need for earlier detection, more accurate non-invasive diagnostics, and the development of targeted therapies. While consensus exists on the gravity of the problem, debate continues regarding the optimal strategies for screening, risk stratification, and long-term management of this complex disease.

Promising Avenues in NAFLD Research

The future of NAFLD treatment may lie in precision medicine approaches that target the specific metabolic pathways driving liver fat accumulation and inflammation. Emerging research focuses on the gut-liver axis, genetic determinants of disease susceptibility, and novel biomarkers for early detection. As the medical community moves toward the MASLD framework, there is cautious optimism that a deeper understanding of metabolic dysfunction will eventually translate into effective interventions.

NAFLD Within the Global Metabolic Health Crisis

NAFLD does not exist in isolation but is deeply intertwined with the worldwide epidemics of obesity, type 2 diabetes, and cardiovascular disease. The condition's estimated global prevalence of approximately 32.4% makes it the most common chronic liver disease in the Western world, with the highest rates observed in the Middle East and South America. This metabolic interconnection means that addressing NAFLD requires a systemic approach that tackles the root causes of metabolic dysfunction across populations.

Patient Stories and Clinical Realities

The human impact of NAFLD extends far beyond clinical statistics, as illustrated by cases of non-obese individuals who develop significant liver disease despite having a relatively normal body mass index. Patients with NAFLD face not only the risk of liver cirrhosis and failure but also a markedly elevated risk of cardiovascular disease, which remains the leading cause of death in this population. These real-world cases demonstrate that NAFLD is a complex condition driven by a combination of genetic predisposition and lifestyle factors, requiring personalized management strategies.

What Them2's role in liver fat means

But deleting Them2 only in the liver did not prevent steatosis or glucose intolerance in mice. The lower blood triglyceride and apolipoprotein B100 levels therefore do not, by themselves, show that liver-specific deletion protects against fatty liver.[1]

How the Them2 findings fit with related evidence

The liver-specific mouse findings differ from results in mice lacking Them2 throughout the body: those animals were protected against diet-induced obesity, steatosis and insulin resistance, while liver-specific deletion left mice susceptible. The contrast points to the importance of where Them2 is absent when interpreting its effects.[2]

A separate line of work connects Them2 in skeletal muscle with hepatic steatosis and insulin resistance, and reports that these effects depend on both the enzyme’s catalytic activity and its interaction with PC-TP. This places Them2 in a broader liver-metabolism context, rather than identifying liver-specific deletion as protective.[3]

A systematic review created a database of rodent NAFLD models and found substantial heterogeneity across the models it assessed. That variety is relevant when comparing results from animal research, but does not establish how well any particular result carries over to people.[4]

In a different clinical context, the FDA approved resmetirom for adults with noncirrhotic NASH and moderate to advanced liver scarring, alongside diet and exercise. That approval concerns a defined patient group and treatment; it does not establish Them2 as a therapeutic target.[5]

What remains unresolved about Them2

  • How do Them2’s catalytic activity and interaction with PC-TP combine to shape liver fat and insulin signaling across different tissues?[3]

Terms used in the Them2 findings

VLDL
Very low-density lipoprotein; the cited source describes its triglycerides as a route by which fatty acids are secreted from the liver.[1]

Sources

  1. Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids Into Triglyceride Biosynthesis. (pubmed.ncbi.nlm.nih.gov)
  2. Up-regulation of thioesterase superfamily member 2 in skeletal muscle promotes hepatic steatosis and insulin resistance in mice. (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)
  4. A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD. (pubmed.ncbi.nlm.nih.gov)
  5. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease | FDA (www.fda.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 is the primary function of Thioesterase Superfamily Member 2 (Them2) in the liver?

Them2's main role is to influence how fatty acids are processed in the liver. Specifically, Them2 directs these fatty acids towards triglyceride synthesis. This process is critical because it affects the accumulation of fat within the liver and its subsequent release into the bloodstream via very low-density lipoprotein (VLDL) particles, impacting overall lipid metabolism and the development of non-alcoholic fatty liver disease (NAFLD).

2

How does Them2's function relate to the development of Non-Alcoholic Fatty Liver Disease (NAFLD)?

Them2 is closely linked to NAFLD because it influences the balance of fat in the liver. By directing fatty acids towards triglyceride synthesis, Them2 can contribute to the accumulation of triglycerides within liver cells, a hallmark of NAFLD. Elevated levels of THEM2 were found in the livers of obese patients with NAFLD. This process disrupts the normal balance between fatty acid accrual and elimination, leading to the disease. If the liver is unable to handle the fat, it starts to accumulate, leading to metabolic complications associated with NAFLD.

3

What were the key findings when scientists studied mice with a liver-specific deletion of the Them2 gene (L-Them2)?

Studies on L-Them2 mice revealed several important findings. Although these mice were not protected against weight gain or glucose intolerance, they showed reduced rates of VLDL secretion, indicating that Them2 influences the liver's ability to export fats into the bloodstream. Also, it was noted that the absence of hepatic steatosis in L-Them2 mice was attributed to increased rates of fatty acid oxidation and decreased de novo lipogenesis (the creation of new fat) in high-fat-fed mice. This suggests that in the absence of Them2, the liver compensates by altering how it processes fats, leading to different metabolic outcomes.

4

Besides the liver, where else is Them2 expressed, and why is this significant?

Them2 is also highly expressed in other oxidative tissues. Although the text focuses on the liver, Them2’s presence in other tissues suggests its broader impact on metabolic processes. The significance lies in the potential for Them2 to affect fat metabolism across multiple organ systems, influencing overall health beyond just liver function. While the research in the text primarily focuses on the liver, understanding the broader impact of Them2 could reveal more about its overall physiological role and lead to therapies for a wider range of metabolic disorders.

5

In what ways could targeting Them2 be a therapeutic approach for NAFLD and related metabolic disorders?

Targeting Them2 offers a promising therapeutic strategy by influencing how the liver processes and manages fats. By modulating Them2 activity, scientists could potentially reduce the accumulation of triglycerides within the liver, a core feature of NAFLD. This could be achieved by either inhibiting Them2 to reduce triglyceride synthesis or by enhancing its activity in a controlled manner to alter fat metabolism. The key is to understand how Them2 influences VLDL secretion and the balance between fatty acid synthesis and oxidation, offering opportunities to develop treatments that improve liver health and address related metabolic issues.

Newsletter Subscribe

Subscribe to get the latest articles and insights directly in your inbox.