Hepatic-specific Pgc-1α ablation drives fibrosis in a MASH model

Area of Science:

• Hepatology
• Mitochondrial Biology
• Metabolic Diseases

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by fat accumulation, inflammation, and fibrosis.
• Mitochondrial dysfunction and oxidative stress are key contributors to MASH pathogenesis.
• Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is crucial for mitochondrial and oxidative metabolism, particularly during fasting.

Purpose of the Study:

• To investigate the role of PGC-1α in the development of MASH.
• To determine the relationship between hepatic PGC-1α expression and MASH.
• To elucidate the mechanistic link between PGC-1α, mitochondrial function, and MASH progression.

Main Methods:

• Measured hepatic PGC-1α expression in human MASH patients and mice on a Western diet (WD).
• Generated a liver-specific PGC-1α knockout mouse model.
• Fed knockout mice a WD with sugar water to induce a MASH-like phenotype.

Main Results:

• Hepatic PGC-1α expression was significantly reduced in MASH patients and mice.
• Liver-specific PGC-1α ablation markedly reduced mitochondrial respiratory capacity.
• PGC-1α deficiency exacerbated MASH-related inflammation, fibrosis, and oxidative stress.
• The profibrotic phenotype occurred independently of obesity, insulin resistance, and lipid imbalance.

Conclusions:

• Hepatic PGC-1α deficiency drives liver fibrosis in MASH independent of lipid and glucose metabolism.
• Mitochondrial dysfunction, mediated by PGC-1α, plays a critical and specific role in MASH development.
• These findings offer new insights into the mechanisms underlying MASH pathogenesis.