Carbon dioxide regulates cholesterol levels through SREBP2

In mammals, O(2) and CO(2) levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O(2) sensing are well characterized, little is known regarding the signaling pathways that participate in CO(2) signaling and adaptation. Here, we show that CO(2) levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO(2) regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO(2) triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO(2) signaling and that cellular cholesterol levels can be modulated by CO(2) through SREBP2.