Carbon dioxide regulates cholesterol levels through SREBP2

In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2. In mammals, oxygen and carbon dioxide levels are tightly regulated and are altered under various pathological conditions, but little is known regarding the pathways involved in CO2 signaling and adaptation. This study provides new insight into the interaction between carbon dioxide, SREBP2 activation and regulation of cholesterol levels, suggesting that cellular cholesterol levels can be modulated by carbon dioxide through SREBP2.