Carbon dioxide regulates cholesterol levels through SREBP2

Abstract

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.

A tale of 2 gasses, 1 regulator, and cholesterol homeostasis

“…Another recent study [5] reported low O 2 (hypoxia) shuts down the SREBP2 pathway by promoting the ubiquitination and degradation of this transcription factor (TF). However, here the mechanism is very different since Bolshette and colleagues [2] found low CO 2 did not affect SREBP2 stability, but rather, low CO 2 activates SREBP2 target genes by reducing cholesterol in the ER. Accordingly, Bolshette and colleagues [2] found that further depleting cell cholesterol by using cyclodextrin blunted the effect of low CO 2 .…”

“…Given the centrality of CO 2 to our metabolism, perhaps it is not surprising roles are emerging for this previously dismissed waste product in key metabolic pathways, including those involving cholesterol. In this issue of PLOS Biology [2], Bolshette and colleagues link CO 2 levels to the master transcriptional regulator of cholesterol homeostasis, Sterol Regulatory Element Binding Protein-2 (SREBP2).…”

“…Bolshette and colleagues [2] discovered a reduction in CO 2 results in the activation of SREBP2 through decreased levels of cholesterol in the ER via an unknown mechanism. Firstly, using cultured murine fibroblasts as their main cell model, they identified genes with altered transcription in response to changing CO 2 levels.…”

“…SREBP2 activates transcription of target genes by binding to sterol regulatory elements (SREs) within promoters of genes. Employing an SRE luciferase reporter assay, Bolshette and colleagues [2] observed increased luminescence over time under low CO 2 conditions in cells expressing a wild-type (but not mutated) SRE reporter. This effect was reversible, luminescence fading away when CO 2 levels returned to 5% from 1%.…”

Orphan Nuclear Receptor Family 4A (NR4A) Members NR4A2 and NR4A3 Selectively Modulate Elements of the Monocyte Response to Buffered Hypercapnia

“…Metacore transcription factor analysis revealed a notable conservation of interactions between several transcription factors, including AML1, SOX17, TAL1, ETS1, and LMO2 ( Supplementary Table S5 ). Transcription factors previously linked with hypercapnia were also identified in our list but were not among the most prominent hits in our model, e.g., Transcription Factor P65 (RelA) [ 29 ], NFκB Subunit 2 (NFKB2) [ 22 ], Hypoxia Inducible Factor 1 Alpha (HIF1α) [ 37 ], Heat Shock Transcription Factor 1 (HSF1) [ 35 ], Cyclic AMP-Responsive Element-Binding Protein 1 (CREB) [ 38 ], Forkhead Box O3 (FOXO3a) [ 39 ], Early Growth Response 2 (EGR2) [ 40 ], Sterol Regulatory Element Binding Transcription Factor 2 (SREBP2) [ 41 ].…”