Loss of liver GH signaling causes lean fatty liver

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects approximately 25% of the global population and is typically linked to obesity. Notably, emerging evidence indicates that 12%–20% of MAFLD occurs in individuals with normal body weight or even in lean individuals, a condition termed lean MAFLD. These individuals often exhibit distinct clinical features, including lower insulin resistance but similar risks of liver fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), and higher cardiovascular mortality. Despite its clinical significance, the underlying mechanism of lean MAFLD remains poorly understood due to the lack of representative animal models.

Clinical studies have linked reduced circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels with hepatic steatosis. Patients with GH deficiency or dysfunctional GH receptor (GHR), such as those with Laron syndrome, are prone to MAFLD. However, the causal role of hepatic GHR signaling in lean MAFLD pathogenesis has remained unclear.

A recent study published in Life Metabolism by Wu et al. from Dalian Medical University addresses this knowledge gap. The researchers developed a liver-specific Ghr knockout (LGHRKO) mouse model that faithfully recapitulates key features of human lean MAFLD. Their findings reveal that CD36-mediated lipid uptake and C/EBPβ-driven lipogenesis form a central regulatory hub driving the disease, providing new mechanistic insight and potential therapeutic targets for lean MAFLD.

The research team first generated hepatocyte-specific Ghr knockout (LGHRKO) mice to investigate the role of hepatic GH signaling. Compared with control and diet-induced obese (DIO) mice, LGHRKO mice maintained normal body weight and reduced adiposity, yet developed hepatomegaly, dyslipidemia, and hepatic insulin resistance due to impaired PI3K/Akt/mTOR signaling, closely mirroring the metabolic features of human lean MAFLD. These mice exhibited a characteristic “low IGF-1, high GH” hormonal profile. Histological analyses further revealed marked hepatic steatosis, hepatocyte ballooning, and inflammation, which progressively advanced to MASH with collagen deposition in older animals.

Mechanistically, the study highlights a central role for the liver–adipose tissue axis in driving lean fatty liver disease. Loss of hepatic GHR created a high-GH hormonal state, which strongly promoted lipolysis in adipose tissue, releasing large amounts of free fatty acids (FFAs) into the circulation. These FFAs were then taken up by the liver through CD36, a fatty acid transporter whose expression was markedly increased in GHR-deficient hepatocytes (Figure 1). Single-cell RNA sequencing revealed that this upregulation was driven by enhanced activity of the transcription factor C/EBPβ, 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.

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

Together, these results establish the LGHRKO mouse as a valuable model for studying lean MAFLD and identify CD36 and C/EBPβ as promising therapeutic targets for future interventions.