Objectives: To investigate potential lipotoxicity associated with severe hypertriglyceridemic (HTG) mice of homozygous LPL gene deletion rescued by somatic gene transfer.Methods: Plasma lipids and aortic lesions were measured.Macrophage adhesion to endothelial cells was quantitated in presence of chylomicrons (CM).Pancreatitis in these mice was induced by cerulin.Acinar cell damages were assessed.Learning and memory was analyzed in water maze.Structural alterations in the brain were determined morphologically.Results:LPL deficient mice on normal diet developed spontaneous atherosclerosis at age over 15 months.High levels of oxidative products in plasma and CM were detected.CMs from old mice significantly increased activation of macrophage adhesion to endothelial cells and VCAM1/MCP1 up-regulation.Similar to LPL deficient patients,these mice have increased susceptibility to acute pancreatitis.In cultured pancreatic acinar cells addition of CM caused stimulation of amylase release, irreversible Ca2+ release and cell damage.This effect was decreased in the presence of the lipase inhibitor orlistat.After discovery of learning and memory deficit in these mice the significant decrease of pre-synaptic vesicles in hippocampi was revealed.Furthermore, synaptophysin, one of the most important pre-synaptic marker, was also reduced significantly.Conclusions: The functional and morphological alterations in multi-organs implicated that severe HTG might exert lipotoxicity via certain common mechanisms to induce organ injury, which will provide new insight into lipid-related cellular stress.