Hepatocyte-Specific Growth Hormone Receptor Ablation Associates with Accelerated Aging and Hepatic Mitochondrial Dysfunction in Mice

Researchers reported that hepatocyte-specific growth hormone receptor deletion in mice accelerates systemic aging phenotypes through a dysregulated lipid-mitochondrial axis that can be ameliorated by targeting PDK4.

Researchers investigated the impact of hepatocyte-specific GHR knockout (LiGHR-/-) in male mice under natural aging and high-fat diet (HFD) conditions.

Male LiGHR-/- mice exhibited accelerated aging-related phenotypes, including shortened lifespan, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging.

Loss of hepatic GHR caused elevated circulating growth hormone (GH) levels, promoting adipose lipolysis and CD36-dependent hepatic steatosis.

At the molecular level, hepatic GHR deficiency impaired STAT5b phosphorylation, upregulating PPARγ, which transcriptionally activated Cd36 and Pdk4, leading to mitochondrial structural damage, increased ROS, and impaired cellular respiration.

Weekly administration of a PDK4-specific inhibitor (PDK4-IN) at 5 mg/kg or 10 mg/kg to 20-month-old LiGHR-/- mice for 16 weeks reduced cellular senescence markers (p16, p21, and γH2AX) and ameliorated hepatic steatosis, inflammation, and fibrosis.

The findings establish a tissue-specific paradigm for growth hormone signaling in aging; unlike global or adipocyte-targeted GHR deletions, hepatocyte GHR ablation leads to systemic physiological decline.

The study maps the precise p-STAT5b-PPARγ-PDK4 signaling pathway that mediates lipid-driven mitochondrial dysfunction and cellular senescence in hepatocytes.

The results validate the therapeutic feasibility of targeting PDK4 to interrupt the self-amplifying cycle of ectopic lipid accumulation and mitochondrial decay, which are core drivers of metabolic dysfunction-associated steatotic liver disease (MASLD) and systemic senescence.

This research refines the therapeutic thesis for drug developers targeting the GH/IGF-1 axis, suggesting that systemic or liver-specific GHR inhibition may cause hepatic and metabolic complications.

The positive in vivo therapeutic outcome of PDK4-IN could accelerate preclinical development and direct investment toward selective PDK4 inhibitors to combat liver-intrinsic and systemic aging.

Further translational validation of PDK4 inhibitors in non-GHR-knockout models of aging to evaluate long-term safety profiles.

The implementation of inducible hepatocyte-specific GHR knockout models to isolate liver-intrinsic aging pathways from the systemic endocrine effects of elevated circulating growth hormone.