Moon 2021 J Lipid Res
| Moon SH, Dilthey BG, Liu X, Guan S, Sims HF, Gross RW (2021) High-Fat diet activates liver iPLA2Ξ³ generating eicosanoids that mediate metabolic stress. J Lipid Res [Epub ahead of print]. |
Moon SH, Dilthey BG, Liu X, Guan S, Sims HF, Gross RW (2021) J Lipid Res
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 A2Ξ³ (iPLA2Ξ³) 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 iPLA2Ξ³ in mitochondrial function and cell death under metabolic stress, we generated a hepatocyte-specific iPLA2Ξ³-knockout (HEPiPLA2Ξ³KO). Using this model, we compared the effects of HF-diet on wild-type vs. HEPiPLA2Ξ³KO mice in the eicosanoid production and mitochondrial bioenergetics. HEPiPLA2Ξ³KO 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 HEPiPLA2Ξ³KO. Furthermore, HF-feeding markedly increased Ca2+ sensitivity and resistance to ADP-mediated inhibition of mPTP opening in WT mice. In contrast, ablation of iPLA2Ξ³ 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, HEPiPLA2Ξ³KO hepatocytes were resistant to calcium ionophore-induced lipoxygenase-mediated LDH release. Collectively, these results demonstrate that HF-diet increases iPLA2Ξ³-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death. β’ Keywords: Cell death, Diet and dietary lipids, Eicosanoids, Hepatocyte, Hydroxyeicosatetraenoic acids, Mitochondria, Mitochondrial permeability transition pore, Mitochondrial respiration, Obesity, Phospholipases A(2) β’ Bioblast editor: Plangger M
Labels: MiParea: Respiration, Exercise physiology;nutrition;life style
Pathology: Obesity
HRR: Oxygraph-2k
2021-03
