Collectively, the results of this study demonstrate that hepatic iPLA2γ plays central roles in HF diet–induced pathologic alterations by providing AA and/or AA-lysophospholipids to 12-LOX for detrimental 12-HETE production that promotes the opening probability of the mPTP and disrupts mitochondrial bioenergetics leading to metabolic stress and the initiation of cell death. The gene discussed is PNPLA8; the disease is hydrops fetalis.