Moon 2021 J Lipid Res
|Moon SH, Dilthey BG, Liu X, Guan S, Sims HF, Gross RW (2021) High-Fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress. J Lipid Res [Epub ahead of print].|
Abstract: High-fat (HF)-diet-induced obesity accompanies 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 under metabolic stress, we generated a hepatocyte-specific iPLA2γ-knockout (HEPiPLA2γKO). Using this model, we compared the effects of HF-diet on wild-type vs. HEPiPLA2γKO mice in the eicosanoid production and mitochondrial bioenergetics. HEPiPLA2γγKO 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 LDH release. Collectively, these results demonstrate that HF-diet increases iPLA2γ-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death.
• Keywords: Cell death, Diet and dietary lipids, Eicosanoids, Hepatocyte, Hydroxyeicosatetraenoic acids, Mitochondria, Mitochondrial permeability transition pore, Mitochondrial respiration, Obesity, Phospholipases A(2) • Bioblast editor: Plangger M • O2k-Network Lab: US MO St Louis Gross RW
Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style Pathology: Obesity
Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS HRR: Oxygraph-2k