Gordon, L. I. | bioRxiv Science

bioRxiv2024

Physiologic Regulation of Lipid Oxidation and Ferroptosis By Vitamin E, High-Density Lipoprotein, and Scavenger Receptor Class B Type 1

Ferroptosis is a form of cell death caused by oxidative (-OOH) damage to phospholipids (PL) that comprise the cell membrane. Understanding mechanisms of ferroptosis is important because of the role it plays in human disease, including cancer and neurodegeneration. Previous work has focused on the intracellular antioxidant enzyme glutathione peroxidase 4 (GPx4), which detoxifies PL-peroxides (PL-OOH) and prevents ferroptosis. Studies also show that alpha-tocopherol (-toc), the active form of Vitamin E, is an exogenous lipophilic antioxidant that inhibits ferroptosis in cancer cells in vitro and in neurons and hematopoietic stem cells in vivo. The mechanisms by which -toc engages cells to manipulate PL redox balance and ferroptosis are unknown. Lipoproteins, like high- and low-density lipoproteins (HDL and LDL), carry -toc in the circulation, which compelled our investigation of their role in -toc delivery and ferroptosis. Using cancer and neuronal cell models, here we show that lipoproteins, particularly HDL, deliver -toc by binding the cell membrane receptor scavenger receptor class B type 1 (SR-B1) to prevent ferroptosis. Additionally, we synthesized SR-B1 targeted HDL-like particles that contained -toc to validate data obtained with native lipoproteins. We reveal here a tunable cellular redox axis whereby native and synthetic HDLs containing -toc target SR-B1 to reduce PL-OOH and prevent ferroptosis.

cell biology↗

bioRxiv2020

Targeting Scavenger Receptor Type B1 In Cholesterol-Addicted Lymphomas Abolishes Glutathione Peroxidase 4 and Results in Ferroptosis

Normal human cells can either synthesize or uptake cholesterol from lipoproteins to meet their metabolic requirements. Some malignant cells absolutely require cholesterol uptake from lipoproteins for survival because de novo cholesterol synthesis genes are transcriptionally silent or mutated. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also dependent on the expression of the lipid hydroperoxidase enzyme glutathione peroxidase 4 (GPX4) to prevent cell death by ferroptosis. Ferroptosis is an oxygen-and iron-dependent cell death mechanism that results from the accumulation of oxidized lipids in cell membranes. To study mechanisms linking cholesterol uptake with ferroptosis, we employed lymphoma cell lines known to be sensitive to cholesterol uptake depletion and treated them with high-density lipoprotein-like (HDL) nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand of the receptor for cholesterol-rich HDL, scavenger receptor type B-1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells favoring de novo cholesterol synthesis, which is accompanied by reduced expression of GPX4. As a result, accumulation of oxidized membrane lipids leads to cell death through a mechanism consistent with ferroptosis. Furthermore, ferroptosis was validated in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake addicted lymphoma cells abolishes GPX4 and cancer cell death ensues through a mechanism consistent with ferroptosis.

cancer biology↗