Deletion of hepatic growth hormone receptor contributes to the pathogenesis of lean MAFLD by elevating CD36.

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disease worldwide, affecting both obese and non-obese individuals. While the reduced levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been consistently observed in patients with hepatic steatosis, the molecular role of hepatic growth hormone receptor (GHR) in MAFLD pathogenesis remains unclear. In this study, we established a liver-specific Ghr knockout (LGHRKO) mouse model that faithfully recapitulates non-obese MAFLD, characterized by hepatomegaly, elevated serum lipids and transaminases, and pronounced hepatic lipid accumulation, all occurring in the absence of obesity or increased adiposity. Mechanistically, LGHRKO livers displayed enhanced lipogenesis, impaired lipolysis, and upregulated cluster of differentiation 36 (CD36) expression, thereby driving hepatic lipid deposition. Single-cell RNA sequencing (scRNA-seq) further revealed hepatocyte-specific transcriptional alterations, including activation of lipid metabolic pathways and dysregulation of autophagy-related processes, providing insights into the cellular mechanisms underlying disease progression. Complementary human genetic analyses, including two-sample Mendelian randomization (MR) and genome-wide association studies (GWASs), demonstrated a causal relationship between impaired GH-IGF signaling and susceptibility to MAFLD, thereby bridging experimental observations with human disease risk. Collectively, our findings identify hepatic GHR deficiency as a key driver of non-obese MAFLD, establish LGHRKO mice as a valuable model for mechanistic and therapeutic studies, and underscore the translational significance of GH-IGF signaling in metabolic liver disease.