High-fat diet activates liver iPLA₂γ generating eicosanoids that mediate metabolic stress

Area of Science:

• Mitochondrial Biology
• Metabolic Disorders
• Cell Death Pathways

Background:

• High-fat (HF) diets induce obesity and metabolic disorders, including insulin resistance and cell death.
• Calcium-independent phospholipase A2γ (iPLA2γ) plays a role in metabolic regulation and mitochondrial function.
• Previous studies showed germline iPLA2γ knockout mice are protected from HF diet-induced metabolic dysfunction.

Purpose of the Study:

• To investigate the specific role of hepatic iPLA2γ in mitochondrial function and cell death under metabolic stress.
• To compare the effects of an HF diet on wild-type (WT) versus hepatocyte-specific iPLA2γ-knockout (HEPiPLA2γKO) mice.

Main Methods:

• Generation of hepatocyte-specific iPLA2γ-knockout (HEPiPLA2γKO) mouse model.
• Comparison of WT and HEPiPLA2γKO mice fed an HF diet, assessing glucose tolerance, eicosanoid production, and mitochondrial bioenergetics.
• Measurement of mitochondrial permeability transition pore (mPTP) opening, mitochondrial respiration, and hepatocyte cell death markers.

Main Results:

• HEPiPLA2γKO mice exhibited improved glucose clearance rates compared to WT controls.
• HF diet increased hepatic 12-hydroxyeicosatetraenoic acid (12-HETE) in WT mice, but this was reduced in HEPiPLA2γKO mice.
• Ablation of hepatic iPLA2γ prevented HF-induced hypersensitivity of mPTP opening to calcium and maintained ADP-mediated resistance, while 12-HETE impaired mitochondrial respiration and promoted cell death.

Conclusions:

• Hepatic iPLA2γ mediates the detrimental effects of an HF diet by increasing 12-HETE production.
• This iPLA2γ-dependent pathway leads to mitochondrial dysfunction, characterized by altered mPTP opening and impaired respiration.
• Targeting hepatic iPLA2γ may offer a therapeutic strategy to prevent HF diet-induced metabolic disorders and liver cell death.