High-fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress
| العنوان: | High-fat diet activates liver iPLA2γ generating eicosanoids that mediate metabolic stress |
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| المؤلفون: | Shaoping Guan, Xinping Liu, Richard W. Gross, Harold F. Sims, Beverly Gibson Dilthey, Sung Ho Moon |
| المصدر: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100052-(2021) |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, obesity, Bioenergetics, AA, arachidonic acid, 030204 cardiovascular system & hematology, Mitochondrion, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, hydroxyeicosatetraenoic acids, 0302 clinical medicine, Endocrinology, mitochondrial respiration, EET, epoxyeicosatrienoic acid, HEPiPLA2γKO, hepatocyte-specific iPLA2γ-knockout, NDGA, nordihydroguaiaretic acid, ANT, adenine nucleotide translocase, LOX, lipoxygenase, LDH, lactate dehydrogenase, MPTP, phospholipases A2, mitochondria, cell death, NC, normal-chow, diet and dietary lipids, Research Article, medicine.medical_specialty, Programmed cell death, TAG, triacylglycerol, mPTP, mitochondrial permeability transition pore, QD415-436, Diet, High-Fat, eicosanoids, 03 medical and health sciences, Insulin resistance, HF, high-fat, Internal medicine, HETE, hydroxyeicosatetraenoic acid, FFA, free fatty acid, medicine, hepatocyte, FCCP, 2-[2-[4-(trifluoromethoxy)phenyl]hydrazinylidene]-propanedinitrile, iPLA2γ, calcium-independent phospholipase A2γ, mitochondrial permeability transition pore, Cell Biology, medicine.disease, AMPP, N-(4-aminomethylphenyl) pyridinium, 030104 developmental biology, chemistry, Mitochondrial permeability transition pore, Hepatic stellate cell, Oxidative stress |
| الوصف: | 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 under metabolic 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 an HF diet increases iPLA2γ-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death. |
| اللغة: | English |
| تدمد: | 1539-7262 0022-2275 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ac707a6479481fac40eba79f66d3ab5b http://europepmc.org/articles/PMC8010217 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ac707a6479481fac40eba79f66d3ab5b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15397262 00222275 |
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