Key mediator of lipid-induced endoplasmic reticulum stress identified
MedWire News: Reducing lipotoxic endoplasmic reticulum (ER) stress in macrophages by targeting the lipid chaperone aP2 ameliorates atherosclerosis, a study in mice has found.
The findings could potentially lead to new therapies for cardiovascular disease, say Gökhan Hotamisligil (Harvard School of Public Health, Boston, Massachusetts, USA) and colleagues in the journal Nature Medicine.
Hotamisligil and team used apolipoprotein-deficient mice to study the mechanisms underlying lipid-induced ER stress, which has recently been identified as a major pathophysiologic paradigm in chronic metabolic disease.
They first showed that the administration of a chemical chaperone, 4-phenyl butyric acid, to alleviate ER stress resulted in marked protection against lipotoxic death in macrophages and also prevented macrophage expression of fatty acid–binding protein-4 (aP2).
The latter finding was “unexpected and striking,” say the researchers.
Subsequent experiments confirmed that aP2 was the predominant regulator of lipid-induced macrophage ER stress, and that mice genetically lacking lipid chaperones had increased production of lipids that rendered their macrophages resistant to lipid-induced ER stress.
The ability of macrophages to defend against lipotoxic ER stress is a “unique metabolic adaptation” that allows lipid chaperones to function as “molecular sensors” for fatty acids and as a “central coordinator” of metabolic ER stress, the researchers observe.
Finally, the team showed that the impact of aP2 on macrophage lipid metabolism and the ER stress response was mediated by upregulation of key lipogenic enzymes by the liver X receptor.
“We have uncovered a previously unknown function for aP2 in lipid-induced ER stress signaling in macrophages,” Hotamisligil et al conclude.
“Because aP2 deficiency can alleviate the ER stress that occurs during atherosclerosis, similar to the actions of a chemical chaperone, our findings offer insights into the detrimental role of macrophage ER stress in atherosclerosis and the benefits of addressing this target to treat cardiovascular disease.”
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By Joanna Lyford