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

Sung Ho Moon, Beverly Gibson Dilthey, Xinping Liu, Shaoping Guan, Harold F. Sims, Richard W. Gross

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


High-fat (HF) diet-induced obesity precipitates multiple metabolic disorders including insulin resistance, glucose intolerance, oxidative stress, and inflammation, resulting in the initiation of cell death programs. Previously, we demonstrated murine germline knockout of calcium-independent phospholipase A2γ (iPLA2γ) prevented HF diet-induced weight gain, attenuated insulin resistance, and decreased mitochondrial permeability transition pore (mPTP) opening leading to alterations in bioenergetics. To gain insight into the specific roles of hepatic iPLA2γ in mitochondrial function and cell death undermetabolic stress, we generated a hepatocyte-specific iPLA2γ- knockout (HEPiPLA2γKO). Using this model, we compared the effects of an HF diet on wild-type versus HEPiPLA2γKO mice in eicosanoid production and mitochondrial bioenergetics. HEPiPLA2γKO mice exhibited higher glucose clearance rates than WT controls. Importantly, HF-diet induced the accumulation of 12-hydroxyeicosatetraenoic acid (12-HETE) in WT liver which was decreased in HEPiPLA2γKO. Furthermore, HF-feeding markedly increased Ca2+ sensitivity and resistance to ADP-mediated inhibition of mPTP opening in WT mice. In contrast, ablation of iPLA2γ prevented the HF-induced hypersensitivity of mPTP opening to calcium and maintained ADP-mediated resistance to mPTP opening. Respirometry revealed that ADP-stimulated mitochondrial respiration was significantly reduced by exogenous 12-HETE. Finally, HEPiPLA2γKO hepatocytes were resistant to calcium ionophore-induced lipoxygenase-mediated lactate dehydrogenase release. Collectively, these results demonstrate that anHF diet increases iPLA2γ-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death.

Original languageEnglish
Article number100052
JournalJournal of lipid research
StatePublished - 2021


  • Cell death
  • Diet and dietary lipids
  • Eicosanoids
  • Hepatocyte
  • Hydroxyeicosatetraenoic acids
  • Mitochondria
  • Mitochondrial permeability transition pore
  • Mitochondrial respiration
  • Obesity
  • Phospholipases A2


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