4-Hydroxynonenal from Mitochondrial and Dietary Source Causes Lysosomal Cell Death for Lifestyle-related Diseases

Excessive consumption of vegetable oils such as soybean and canolla oils containing ω-6 polyunsaturated fatty acids, is considered one of the most important epidemiological factors leading to the progression of lifestyle-related diseases. However, the underlying mechanism of vegetable oil-induced organ damage is incompletely elucidated. Since proopiomelanocortin (POMC) neurons in the hypothalamus are related to the control of appetite and energy expenditure, their cell degeneration/death is crucial for the occurrence of obesity. In the patients with metabolic syndrome, saturated fatty acid especially palmitate is used as an energy source. Since abundant reactive oxygen species are produced during β-oxidation of the palmitate in mitochondria, an increased amount of 4-hydroxy-2-nonenal (4-HNE) is endogenously generated from linoleic acids constituting cardiolipin of the inner membranes. Further, due to the daily intake of deep-fried foods and/or high-fat diets cooked by vegetable oils, exogenous 4-HNE being generated via lipid-peroxidation during heating, is incorporated into the blood. By binding with atheromatous and/or senile plaques, 4-HNE inactivates proteins via forming hybrid covalent chemical addition compounds, and causes cellular dysfunction and tissue damage by the specific oxidation, carbonylation. 4-HNE overstimulates G protein-coupled receptors to induce abnormal Ca2+ mobilization and µ-calpain activation. These endogenous and exogenous 4-HNE synergically causes POMC neuronal degeneration/death and obesity. Then, the resultant metabolic disorder facilitates degeneration/death of hippocampal neurons, pancreatic β-cells, and hepatocytes. Hsp70.1 is a molecular chaperone which is crucial for both the protein quality control and the stabilization of lysosomal limiting membranes. Focusing the monkey hippocampus after ischemia, previously we formulated the ‘calpain-cathepsin hypothesis’, i.e., calpain-mediated cleavage of carbonylated Hsp70.1 is a trigger of programmed neuronal death. This review aims to report that in diverse organs lysosomal cell degeneration/death occurs via the calpain-cathepsin cascade after the consecutive injections of synthetic 4-HNE in monkeys. Presumably, 4-HNE is a root substance of lysosomal cell death for lifestyle-related diseases.