Scientists have identified why some people with normal body weight develop fatty liver disease, a condition that affects 12 to 20 percent of lean individuals worldwide and carries similar risks of liver damage as obesity-related cases. A recent study published in Life Metabolism by researchers at Dalian Medical University developed a mouse model that closely mirrors human lean metabolic dysfunction-associated fatty liver disease (lean MAFLD), revealing that impaired growth hormone (GH) signaling in the liver drives the disease through a specific molecular pathway.

What Is Lean Fatty Liver Disease and Why Does It Matter?

Metabolic dysfunction-associated fatty liver disease, or MAFLD, affects approximately 25 percent of the global population. While most people assume fatty liver disease only affects those with obesity, emerging evidence shows that 12 to 20 percent of cases occur in individuals with normal body weight or even lean individuals. These lean patients often have lower insulin resistance but face similar risks of developing metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and higher cardiovascular mortality compared to their obese counterparts.

Despite its clinical significance, the underlying mechanism of lean MAFLD has remained poorly understood due to the lack of animal models that accurately represent the human condition. This knowledge gap has made it difficult for researchers to develop targeted treatments for this population.

How Does Growth Hormone Loss Trigger Fatty Liver in Lean People?

The new research provides a breakthrough explanation. Clinical studies have long linked reduced circulating growth hormone and insulin-like growth factor 1 (IGF-1) levels with hepatic steatosis, or fatty liver. Patients with growth hormone deficiency or dysfunctional growth hormone receptor, such as those with Laron syndrome, are prone to MAFLD. However, the causal role of hepatic growth hormone receptor signaling in lean MAFLD pathogenesis had remained unclear until now.

The research team generated hepatocyte-specific growth hormone receptor knockout (LGHRKO) mice to investigate the role of hepatic growth hormone signaling. Compared with control and diet-induced obese mice, LGHRKO mice maintained normal body weight and reduced adiposity, yet developed hepatomegaly (enlarged liver), dyslipidemia (abnormal blood fat levels), and hepatic insulin resistance due to impaired signaling through the PI3K/Akt/mTOR pathway. These mice exhibited a characteristic "low IGF-1, high GH" hormonal profile that closely mirrored the metabolic features of human lean MAFLD.

Histological analyses revealed marked hepatic steatosis, hepatocyte ballooning (swelling of liver cells), and inflammation, which progressively advanced to MASH with collagen deposition in older animals, demonstrating that the condition can worsen over time.

The Liver-Adipose Tissue Axis: Understanding the Molecular Mechanism

The study highlights a central role for the liver-adipose tissue axis in driving lean fatty liver disease. Loss of hepatic growth hormone receptor created a high-GH hormonal state, which strongly promoted lipolysis in adipose tissue, releasing large amounts of free fatty acids into the circulation. These free fatty acids were then taken up by the liver through CD36, a fatty acid transporter whose expression was markedly increased in growth hormone receptor-deficient hepatocytes.

Single-cell RNA sequencing revealed that this upregulation was driven by enhanced activity of the transcription factor C/EBP-beta, leading to excessive hepatic lipid deposition. Meanwhile, de novo lipogenesis was elevated and lipid breakdown was suppressed, further worsening steatosis. The researchers also identified an activated macrophage population expressing inflammatory mediators such as CCL5, which contributed to liver inflammation and fibrosis.

Steps to Understanding Potential Treatment Targets

• CD36 Inhibition: Blocking the CD36 fatty acid transporter could reduce the uptake of circulating free fatty acids into the liver, potentially preventing or reversing hepatic steatosis in lean individuals with impaired growth hormone signaling.
• C/EBP-beta Modulation: Targeting the transcription factor C/EBP-beta may suppress the excessive lipogenesis driven by growth hormone receptor loss, reducing the liver's ability to accumulate fat.
• Growth Hormone Replacement or Signaling Enhancement: Restoring or enhancing hepatic growth hormone receptor signaling could normalize the hormonal profile and reduce the lipolytic drive from adipose tissue, addressing the root cause of the disease.

What Do Human Genetic Studies Reveal?

Complementary human genetic analyses supported these experimental findings. Two-sample Mendelian randomization demonstrated that lower circulating growth hormone levels were causally linked to an increased risk of MAFLD, emphasizing the clinical relevance of the growth hormone-IGF-1 signaling axis in human disease.

Together, these results establish the LGHRKO mouse as a valuable model for studying lean MAFLD and identify CD36 and C/EBP-beta as promising therapeutic targets for future interventions. The findings suggest that treatment strategies for lean fatty liver disease may need to differ from those developed for obesity-related fatty liver, since the underlying mechanisms are distinct.

How Does This Compare to Other Fatty Liver Interventions?

While this research focuses on the hormonal and molecular drivers of lean MAFLD, other approaches to fatty liver disease have shown promise in different populations. For example, dietary interventions have demonstrated significant benefits in individuals with obesity and prediabetes. A randomized controlled trial conducted at Washington University School of Medicine found that a ketogenic diet reduced liver fat by 67 percent in obese individuals with prediabetes and fatty liver disease, with about 50 percent of participants reversing their prediabetes status despite similar weight loss across different diet groups.

However, the mechanisms driving benefit in obese versus lean populations appear to differ. In obesity-related MAFLD, weight loss and dietary macronutrient composition play central roles. In lean MAFLD, the growth hormone-IGF-1 signaling axis appears to be the primary driver, suggesting that future treatments may need to be tailored to the underlying cause of fatty liver in each patient.

The identification of CD36 and C/EBP-beta as therapeutic targets in lean MAFLD represents a significant step forward in understanding and potentially treating this underrecognized form of liver disease. As researchers continue to validate these findings in human studies, patients with lean fatty liver disease may soon have access to more targeted and effective treatment options.