Abstract
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.
Highlights
Supplemetary key words eicosanoids phospholipases A2 diet and dietary lipids obesity mitochondria mitochondrial respiration mitochondrial permeability transition pore hydroxyeicosatetraenoic acids hepatocyte cell death
Because independent phospholipase A2γ (iPLA2γ) is known to be localized to mitochondrial membranes, we determined if mitochondrial respiration was altered in isolated HEPiPLA2γKO liver mitochondria
Previous work from our laboratory reported that global genetic ablation of iPLA2γ resulted in multicomponent abnormal phenotypes which included compromised mitochondrial ultrastructure and function, insulin hypersensitivity, the inability to gain weight during HF feeding, impaired skeletal muscular respiration and strength, and lower triacylglycerol content in adipose tissue [20]
Summary
Saturated fatty acid-enriched diet–induced obesity commonly results in nonalcoholic fatty liver disease, hyperinsulinemia, impaired glucose tolerance, hypertension, and hepatic cell death through chronic disorders of lipid metabolism. Oxidative stress in the early stages of the obese state is known to contribute to the accumulation of toxic oxidized lipids, uncontrolled opening of the mitochondrial permeability transition pore (mPTP), the synthesis of proinflammatory cytokines, and initiation of cell death programs [6,7,8]. Zhang et al [10] have demonstrated that 12-hydroxyeicosatetraenoic acid (12-HETE), which is produced by 12-lipoxygenase (12-LOX), was generated during hepatic ischemia/ reperfusion injury resulting in inflammation that could be attenuated by inhibition of 12-LOX enzymatic activity. This study collectively demonstrates that hepatic iPLA2γ is a central regulator of diet-dependent production of lipid mediators in hepatocytes and mitochondrial dysfunction during pathologic disease states contributing to hepatocyte cell death pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
