Beyond guarding the cellular proteome the major stress inducible heat shock protein Hsp70 has been shown to interact with lipids. Non-cytosolic Hsp70 stabilizes membranes during stress challenges and, in pathophysiological states, facilitates endocytosis, counteracts apoptotic mechanisms, sustains survival pathways or represents a signal that can be recognized by the immune system. Disease-coupled lipid-associated functions of Hsp70 may be targeted via distinct subcellular localizations of Hsp70 itself or its specific interacting lipids. With a special focus on interacting lipids, here we discuss localization-dependent roles of the membrane-bound Hsp70 in the context of its therapeutic potential, particularly in cancer and neurodegenerative diseases.

Although excessive consumption of deep-fried foods is regarded as 1 of the most important epidemiological factors of lifestyle diseases such as Alzheimer's disease, type 2 diabetes, and obesity, the exact mechanism remains unknown. This review aims to discuss whether heated cooking oil-derived peroxidation products cause cell degeneration/death for the occurrence of lifestyle diseases. Deep-fried foods cooked in ω-6 PUFA-rich vegetable oils such as rapeseed (canola), soybean, sunflower, and corn oils, already contain or intrinsically generate "hydroxynonenal" by peroxidation. As demonstrated previously, hydroxynonenal promotes carbonylation of heat-shock protein 70.1 (Hsp70.1), with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. Until now, the implication of lysosomal/autophagy failure due to the daily consumption of ω-6 PUFA-rich vegetable oils in the progression of cell degeneration/death has not been reported. Since the "calpain-cathepsin hypothesis" was formulated as a cause of ischemic neuronal death in 1998, its relevance to Alzheimer's neuronal death has been suggested with particular attention to hydroxynonenal. However, its relevance to cell death of the hypothalamus, liver, and pancreas, especially related to appetite/energy control, is unknown. The hypothalamus senses information from both adipocyte-derived leptin and circulating free fatty acids. Concentrations of circulating fatty acid and its oxidized form, especially hydroxynonenal, are increased in obese and/or aged subjects. As overactivation of the fatty acid receptor G-protein coupled receptor 40 (GPR40) in response to excessive or oxidized fatty acids in these subjects may lead to the disruption of Ca2+ homeostasis, it should be evaluated whether GPR40 overactivation contributes to diverse cell death. Here, we describe the molecular implication of ω-6 PUFA-rich vegetable oil-derived hydroxynonenal in lysosomal destabilization leading to cell death. By oxidizing Hsp70.1, both the dietary PUFA- (exogenous) and the membrane phospholipid- (intrinsic) peroxidation product "hydroxynonenal," when combined, may play crucial roles in the occurrence of diverse lifestyle diseases including Alzheimer's disease.