Tough neighborhoods can turn a good cell bad. And chronic stress is a bad thing for macrophages, scavenger cells of the immune system.
In atherosclerosis, blood vessels are clogged by fatty materials that lead to the formation of plaques. Macrophages try to come to the rescue by gulping down toxic blood lipids. Despite the good intentions, lipid-gorged, dying macrophages eventually induce plaque instability and rupture, which leads to blood clots and blood flow obstruction.
How do these lipids convert macrophages from heroes into villains?
A new study led by Ebru Erbay, a postdoctoral fellow in the laboratory of Gökhan Hotamisligil, chair of the Department of Genetics and Complex Diseases at HSPH, reveals how toxic lipids cause stress in macrophages and demonstrates that this stress promotes atherosclerosis. The study also identifies a molecule whose inhibition might control this deadly disorder.
The endoplasmic reticulum (ER) is an organelle that can detect many types of cellular stress and serves as a critical regulator of obesity, insulin resistance and diabetes, as discovered in earlier studies by Hotamisligil’s lab. Drugs such as 4-phenyl butyric acid (PBA) or taurine-conjugated ursodeoxycholic acid (TUDCA) reduce ER stress and reverse the destructive reaction it triggers in animal models of obesity. Erbay and colleagues now find that PBA alleviates lipid-induced ER stress and cell death in macrophages. It also reduces vascular lesions in atherosclerotic mice.
The scientists discovered that the beneficial effects of this chemical are based on its inhibition of a lipid chaperone called aP2. Lipid chaperones are molecules that bind to lipids and control their intracellular fates. Previous studies from Hotamisligil’s group found that loss of aP2 protects against atherosclerosis. In fact, mice without aP2 are what Hotamisligil describes as “metabolically bulletproof.”
The current study sheds light on why loss of this lipid chaperone might have such profound benefits and describes a new path that toxic lipids must travel to influence ER function.
Erbay and colleagues found that aP2 is necessary for the ER stress response in macrophages exposed to toxic lipids. They also identified the downstream signaling mechanisms by which aP2 governs ER stress and uncovered a previously unknown phenomenon of new fatty acid synthesis in the macrophage. This de novo fatty acid synthesis was protective, providing resistance to ER stress.
Together these findings may have significant therapeutic implications for metabolic disease beyond atherosclerosis and could even spark the development of dietary interventions for these conditions.
“For a long time, lipotoxicity was thought to be a nonspecific demise of cells,” Erbay noted. She and Hotamisligil agree that their demonstration that lipids engage specific pathways to exert toxic effects through the ER is perhaps one of the most important aspects of the study.
“To our knowledge, this is the first specific molecular pathway mediating lipotoxicity,” said Hotamisligil.
The study appears in the Dec. 15 issue of Nature Medicine.
For more information, students may contact Ebru Erbay at eerbay@hsph.harvard.edu or Gökhan Hotamisligil at ghotamis@hsph.harvard.edu.
