Carbon dioxide regulates cholesterol levels through SREBP2.
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ABSTRACT:
SUBMITTER: Bolshette N
PROVIDER: S-EPMC10651039 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Carbon dioxide regulates cholesterol levels through SREBP2.
Bolshette Nityanand N Ezagouri Saar S Dandavate Vaishnavi V Karavaeva Iuliia I Golik Marina M Wang Hu H Espenshade Peter J PJ Osborne Timothy F TF Han Xianlin X Asher Gad G
PLoS biology 20231115 11
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 ...[more]
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Project description: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 membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2
2023-10-06 | GSE196294 | GEO
Project description:Carbon dioxide regulates cholesterol levels through SREBP2
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Project description:Infection prevention and control (IPC) measures safeguard primary healthcare systems, especially as the infectious disease landscape evolves due to climate and environmental change, increased global mobility, and vaccine hesitancy and inequity, which can introduce unexpected pathogens. This study explores the importance of an "always-on," low-cost IPC approach, focusing on the role of natural ventilation in health facilities, particularly in low-resource settings. Ambient carbon dioxide (CO2) levels are increasingly used as a measure of ventilation effectiveness allowing for spot checks and targeted ventilation improvements. Data were collected through purposive sampling in Northern Ghana over a three-month period. Levels of CO2 ppm (parts per million) were measured by a handheld device in various healthcare settings, including Community-Based Health Planning and Services (CHPS) facilities, municipal and teaching hospitals, and community settings to assess ventilation effectiveness. Analyses compared CO2 readings in community and hospital settings as well as in those settings with and without natural ventilation. A total of 40 facilities were evaluated in this study; 90% were healthcare facilities and 75% had natural ventilation (with an open window, door or wall). Facilities that relied on natural ventilation were mostly community health centers (60% vs 0%) and more commonly had patients present (83% vs 40%) compared with facilities without natural ventilation. Facilities with natural ventilation had significantly lower CO2 concentrations (CO2 ppm: 663 vs 1378, p = 0.0043) and were more likely to meet international thresholds of CO2 < 800 ppm (87% vs 10%, p = <0.0001) and CO2 < 1000 ppm (97% vs 20%, p = <0.0001). The adjusted odds ratio of low CO2 in the natural facilities compared with non-natural were: odds ratios, OR (95% CI): 21.7 (1.89, 247) for CO2 < 800 ppm, and 16.8 (1.55, 183) for CO2 < 1000 ppm. Natural ventilation in these facilities was consistently significantly associated with higher likelihood of low CO2 concentrations. Improved ventilation represents one cost-effective layer of IPC. This study highlights the continuing role natural ventilation can play in health facility design in community health care clinics. Most health facilities met standard CO2 thresholds, particularly in community health facilities. Further research is needed to optimize the use of natural ventilation. The use of a handheld devices to track a simple metric, CO2 levels, could improve appreciation of ventilation among healthcare workers and public health professionals and allow for them to target improvements. This study highlights potential lessons in the built environment of community primary health facilities as a blueprint for low-cost, integrated multi-layer IPC measures to mitigate respiratory illness and anticipate future outbreaks.
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Project description:R-spondins (Rspos) are endogenous ligands of leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4). Rspos-LGR4 signaling plays important roles in embryogenesis, gastrointestinal homeostasis, and food intake. Here, we investigated the impacts of Rspos-LGR4 on hepatic cholesterol synthesis. Rspo1/3 and Lgr4 knockdown mice were used to investigate the impacts of Rspo1/3-LGR4 on hepatic cholesterol synthesis. AMPKα agonist, antagonist, and shRNA were used to explore the downstream targets of Rspos-LGR4 signaling. In our study, we reported that LGR4, Rspo1, and Rspo3 were highly expressed in hepatocytes and their expressions were sensitive to energy states. Rspo1 and Rspo3 reversed OA-induced cholesterol synthesis, accompanying with increased the phosphorylation of AMPKα Thr172, reduced SREBP2 nuclear translocation, and Srebf2 mRNA expression. Conversely, hepatic LGR4 knockdown increased hepatic cholesterol synthesis and decreased the phosphorylation of AMPKα both in vitro and in vivo. Activation or inhibition of AMPKα significantly abolished the effects of LGR4 deficiency or Rspos, respectively, on cholesterol synthesis. Knockdown of AMPKα1 or/and AMPKα2 repressed Rspos-induced inhibition on cholesterol synthesis. Our study indicates that Rspo1/Rspo3-LGR4 signaling in hepatocytes suppresses cholesterol synthesis via the AMPKα-SREBP2 pathway.
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Project description:ImportanceAlterations in the partial pressure of carbon dioxide, arterial (Paco2) can affect cerebral perfusion after traumatic brain injury. End-tidal carbon dioxide (EtCO2) monitoring is a noninvasive tool used to estimate Paco2 values.ObjectiveTo examine the agreement between Paco2 and EtCO2 and associated factors in children with traumatic brain injury.Design, setting, and participantsA secondary analysis was conducted using data from a prospective cohort study of 137 patients younger than 18 years with traumatic brain injury who were admitted to the pediatric intensive care unit of a level I trauma center between May 1, 2011, and July 31, 2017. Analysis was performed from December 17, 2018, to January 10, 2019.Main outcomes and measuresThe closest EtCO2 value obtained within 30 minutes of a Paco2 value and the closest systolic blood pressure value obtained within 60 minutes prior to a Paco2 value during the first 24 hours after admission were recorded. The main outcome of Paco2-EtCO2 agreement was defined as Paco2 between 0 and 5 mm Hg greater than the paired EtCO2 value, and it was determined using Bland-Altman analysis, Passing and Bablok regression, and the Pearson correlation coefficient. Multivariable regression models determined which factors were associated with agreement.ResultsThe analysis included 137 patients (34 girls and 103 boys; mean [SD] age, 10.0 [6.3] years) and 445 paired Paco2-EtCO2 data points. On average, Paco2 was 2.7 mm Hg (95% limits of agreement, -11.3 to 16.7) higher than EtCO2. Overall, 187 of all Paco2-EtCO2 pairs (42.0%) agreed. There was larger variation in the Paco2-EtCO2 difference during the first 8 hours compared with 9 to 24 hours after admission to the pediatric intensive care unit. Development of pediatric acute respiratory distress syndrome within 24 hours of admission was associated with a lower likelihood of Paco2-EtCO2 agreement (adjusted odds ratio, 0.20; 95% CI, 0.08-0.51) compared with no development of pediatric acute respiratory distress syndrome. A diagnosis of pediatric acute respiratory distress syndrome 1 to 7 days after admission was associated with a larger first-day Paco2-EtCO2 difference compared with those who never developed pediatric acute respiratory distress syndrome (mean [SD] difference, 4.48 [3.70] vs 0.46 [5.50] mm Hg).Conclusions and relevanceIn this study of pediatric traumatic brain injury, Paco2-EtCO2 agreement was low, especially among patients with pediatric acute respiratory distress syndrome. Low Paco2-EtCO2 agreement early in hospitalization may be associated with future development of pediatric acute respiratory distress syndrome. Data on EtCO2 should not be substituted for data on Paco2 during the first 24 hours.
| S-EPMC6704750 | biostudies-literature
Project description:BackgroundCarbon dioxide (CO2) inhalation, a biological challenge and pathologic marker in panic disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomic location of CO2-sensing systems that translate CO2-evoked fear remain unclear. We investigated contributions of microglial acid sensor T cell death-associated gene-8 (TDAG8) and microglial proinflammatory responses in CO2-evoked behavioral and physiological responses.MethodsCO2-evoked freezing, autonomic, and respiratory responses were assessed in TDAG8-deficient ((-/-)) and wild-type ((+/+)) mice. Involvement of TDAG8-dependent microglial activation and proinflammatory cytokine interleukin (IL)-1β with CO2-evoked responses was investigated using microglial blocker, minocycline, and IL-1β antagonist IL-1RA. CO2-chemosensitive firing responses using single-cell patch clamping were measured in TDAG8(-/-) and TDAG8(+/+) mice to gain functional insights.ResultsTDAG8 expression was localized in microglia enriched within the sensory circumventricular organs. TDAG8(-/-) mice displayed attenuated CO2-evoked freezing and sympathetic responses. TDAG8 deficiency was associated with reduced microglial activation and proinflammatory cytokine IL-1β within the subfornical organ. Central infusion of microglial activation blocker minocycline and IL-1β antagonist IL-1RA attenuated CO2-evoked freezing. Finally, CO2-evoked neuronal firing in patch-clamped subfornical organ neurons was dependent on acid sensor TDAG8 and IL-1β.ConclusionsOur data identify TDAG8-dependent microglial acid sensing as a unique chemosensor for detecting and translating hypercapnia to fear-associated behavioral and physiological responses, providing a novel mechanism for homeostatic threat detection of relevance to psychiatric conditions such as panic disorder.
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Project description:The growth of rice in submerged soils depends on its ability to form continuous gas channels-aerenchyma-through which oxygen (O2 ) diffuses from the shoots to aerate the roots. Less well understood is the extent to which aerenchyma permits venting of respiratory carbon dioxide (CO2 ) in the opposite direction. Large, potentially toxic concentrations of dissolved CO2 develop in submerged rice soils. We show using X-ray computed tomography and image-based mathematical modelling that CO2 venting through rice roots is far greater than thought hitherto. We found rates of venting equivalent to a third of the daily CO2 fixation in photosynthesis. Without this venting through the roots, the concentrations of CO2 and associated bicarbonate (HCO3 - ) in root cells would have been well above levels known to be toxic to roots. Removal of CO2 and hence carbonic acid (H2 CO3 ) from the soil was sufficient to increase the pH in the rhizosphere close to the roots by 0.7 units, which is sufficient to solubilize or immobilize various nutrients and toxicants. A sensitivity analysis of the model showed that such changes are expected for a wide range of plant and soil conditions.
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Project description:Hepatocyte is a hub for cholesterol metabolism. Augmented synthesis of cholesterol in the liver is associated with hypercholesterolemia and contributes to the pathogenesis of a host of cardiovascular and metabolic diseases. Sterol response element binding protein 2 (SREBP2) regulates hepatic cholesterol metabolism by activating the transcription of rate-limiting enzymes in the cholesterol biosynthesis pathway. The underlying epigenetic mechanism is not well understood. We report here that mice with hepatocyte-specific knockout (CKO) of Brg1, a chromatin remodeling protein, exhibit reduced levels of hepatic cholesterol compared to the wild type (WT) littermates when placed on a high-fact diet (HFD) or a methionine-and-choline-deficient diet (MCD). Down-regulation of cholesterol levels as a result of BRG1 deficiency was accompanied by attenuation of cholesterogenic gene transcription. Likewise, BRG1 knockdown in hepatocytes markedly suppressed the induction of cholesterogenic genes by lipid depletion formulas. Brg1 interacted with SREBP2 and was recruited by SREBP2 to the cholesterogenic gene promoters. Reciprocally, Brg1 deficiency dampened the occupancies of SREBP2 on target promoters likely through modulating H3K9 methylation on the cholesterogenic gene promoters. Mechanistically, Brg1 recruited the H3K9 methyltransferase KDM3A to co-regulate pro-cholesterogenic transcription. KDM3A silencing dampened the cholesterogenic response in hepatocytes equivalent to Brg1 deficiency. In conclusion, our data demonstrate a novel epigenetic pathway that contributes to SREBP2-dependent cholesterol synthesis in hepatocytes.
| S-EPMC7243037 | biostudies-literature
Project description:Sleep deprivation (SD) contributes to cognitive impairment. Astrocytic cholesterol biosynthesis is crucial for brain cholesterol homeostasis and cognitive function. However, the underlying mechanism of astrocytic cholesterol metabolism in SD-induced cognitive impairment has not been fully explored. Trimethylamine N-oxide (TMAO), a product of liver flavin-containing monooxygenase-3 (FMO3), has been shown to be increased in the urine of sleep-deprived humans and implicated with peripheral cholesterol metabolism. Nevertheless, how TMAO affects brain cholesterol metabolism remains unclear. In our study, increased FMO3 and brain TMAO levels were observed in the SD mice, and elevated levels of TMAO were confirmed to lead to SD-induced cognitive dysfunction. In addition, we found that the expression of sterol regulatory element-binding protein 2 (SREBP2) is decreased in the brain of SD mice, resulting in the reduction in brain cholesterol content, which in turn causes synaptic damage. Moreover, we demonstrated that TMAO inhibits the expression of SREBP2. In contrast, FMO3 inhibitor 3,3'-diindolylmethane (DIM) alleviates SD-induced cognitive impairment by targeting the liver-brain axis. In conclusion, our study revealed that the TMAO pathway is involved in memory impairment in SD mice through deregulating astrocytic cholesterol metabolism.
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