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P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers

Yuan Li1, Weiguo Fan1, Tzu-Han Lo1

  • 1Division of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.

The American Journal of Pathology
|December 29, 2024
PubMed

Insights

Shc isoform p46Shc induction in aging impairs mitochondrial function and lipid metabolism, worsening liver injury in metabolic dysfunction-associated steatohepatitis (MASH). Targeting Shc may offer a therapeutic strategy for MASH.

Area of Science:

  • Mitochondrial biology
  • Metabolic disease research
  • Cellular signaling pathways

Background:

  • Mitochondrial dysfunction is a key driver of metabolic dysfunction-associated steatohepatitis (MASH).
  • The Shc protein family, particularly the p46Shc isoform, is implicated in aging-related MASH progression.
  • The in vivo role of p46Shc in regulating lipid metabolism and mitochondrial function in MASH remains unclear.

Purpose of the Study:

  • To investigate the in vivo metabolic consequences of p46Shc induction in the liver.
  • To determine the impact of p46Shc on mitochondrial function, lipid β-oxidation, and oxidative stress in a mouse model of aging and MASH.
  • To explore the therapeutic potential of targeting p46Shc in MASH.

Main Methods:

  • Generation of p46Shc-inducible mice and aging studies.
  • Dietary interventions including chow and high-fat, high-fructose (fast-food) diets.
  • Assessment of liver injury, inflammation, lipid peroxidation, mitochondrial morphology (electron microscopy), oxygen consumption (Oroboros), β-hydroxybutyrate production, and reactive oxygen species (ROS) generation.
  • Evaluation of dominant-negative p46Shc effects on ACAA2 activity and β-oxidation.

Main Results:

  • p46Shc induction exacerbated liver injury, inflammation, and lipid peroxidation in aged mice, particularly on a fast-food diet.
  • Mitochondria displayed swelling and aberrant cristae, with reduced oxygen consumption and suppressed β-hydroxybutyrate production.
  • Increased ROS production was observed, while dominant-negative p46Shc expression improved β-oxidation and reduced oxidative stress.
  • p46Shc overexpression did not significantly alter liver triglyceride levels.

Conclusions:

  • p46Shc induction in aging represses acetyl-coenzyme A acyltransferase 2 (ACAA2), leading to decreased mitochondrial β-oxidation and increased lipid peroxidation.
  • Maintaining mitochondrial β-oxidation and ketogenesis is crucial for preventing liver injury in MASH.
  • Targeting Shc-mediated maladaptive responses presents a promising therapeutic strategy for aging-related MASH.

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