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 62: 100052. [Epub ahead of print].

» PMID: 33636162 Open Access

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

2021-03