Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Subjects and Ethics
2.3. Blood and Tissue Sampling
2.4. Quantification of Circulating Betatrophin/ANGPTL8
2.5. Betatrophin/ANGPTL8 Expression in VAT
2.6. Statistical Analysis
3. Results
3.1. Patient characteristics
3.2. Betatrophin/ANGPTL8 under Conditions of Major Inflammation vs. Isolated Metabolic Dysregulation
3.3. Associations of Betatrophin/ANGPTL8 with Surrogate Parameters of Lipid Metabolism under Conditions of Septic Dyslipidemia
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
- Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.-D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801–810. [Google Scholar] [CrossRef]
- Angus, D.C.; van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 2013, 369, 840–851. [Google Scholar] [CrossRef] [PubMed]
- Singer, M. Critical illness and flat batteries. Crit. Care 2017, 21, 309. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chambrier, C.; Laville, M.; Rhzioual, B.K.; Odeon, M.; Boulétreau, P.; Beylot, M. Insulin sensitivity of glucose and fat metabolism in severe sepsis. Clin. Sci. 2000, 99, 321–328. [Google Scholar] [CrossRef]
- Santos-Baez, L.S.; Ginsberg, H.N. Hypertriglyceridemia-Causes, Significance, and Approaches to Therapy. Front. Endocrinol. 2020, 11, 616. [Google Scholar] [CrossRef] [PubMed]
- Rival, T.; Cinq-Frais, C.; Silva-Sifontes, S.; Garcia, J.; Riu, B.; Salvayre, R.; Genestal, M.; Caspar-Bauguil, S. Alteration of plasma phospholipid fatty acid profile in patients with septic shock. Biochimie 2013, 95, 2177–2181. [Google Scholar] [CrossRef]
- Trinder, M.; Boyd, J.H.; Brunham, L.R. Molecular regulation of plasma lipid levels during systemic inflammation and sepsis. Curr. Opin. Lipidol. 2019, 30, 108–116. [Google Scholar] [CrossRef]
- Walley, K.R. Role of lipoproteins and proprotein convertase subtilisin/kexin type 9 in endotoxin clearance in sepsis. Curr. Opin. Crit. Care 2016, 22, 464–469. [Google Scholar] [CrossRef]
- Kiss, L.; Fűr, G.; Mátrai, P.; Hegyi, P.; Ivány, E.; Cazacu, I.M.; Szabó, I.; Habon, T.; Alizadeh, H.; Gyöngyi, Z.; et al. The effect of serum triglyceride concentration on the outcome of acute pancreatitis: Systematic review and meta-analysis. Sci. Rep. 2018, 8, 14096. [Google Scholar] [CrossRef]
- Golucci, A.P.B.S.; Marson, F.A.L.; Ribeiro, A.F.; Nogueira, R.J.N. Lipid profile associated with the systemic inflammatory response syndrome and sepsis in critically ill patients. Nutrition 2018, 55–56, 7–14. [Google Scholar] [CrossRef]
- Cetinkaya, A.; Erden, A.; Avci, D.; Karagoz, H.; Karahan, S.; Basak, M.; Bulut, K.; Gencer, V.; Mutlu, H. Is hypertriglyceridemia a prognostic factor in sepsis? Ther. Clin. Risk Manag. 2014, 10, 147–150. [Google Scholar] [CrossRef] [Green Version]
- Ke, Y.; Liu, S.; Zhang, Z.; Hu, J. Circulating angiopoietin-like proteins in metabolic-associated fatty liver disease: A systematic review and meta-analysis. Lipids Health Dis. 2021, 20, 55. [Google Scholar] [CrossRef] [PubMed]
- von Loeffelholz, C.; Pfeiffer, A.F.H.; Lock, J.F.; Lieske, S.; Döcke, S.; Murahovschi, V.; Kriebel, J.; de Las Heras Gala, T.; Grallert, H.; Rudovich, N.; et al. ANGPTL8 (Betatrophin) is Expressed in Visceral Adipose Tissue and Relates to Human Hepatic Steatosis in Two Independent Clinical Collectives. Horm. Metab. Res. 2017, 49, 343–349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Luo, M.; Su, X.; Yi, Y.; Yang, Y.; Peng, D. Apolipoprotein CIII may mediate the impacts of angiopoietin-like protein 8 on triglyceride metabolism. Lipids Health Dis. 2018, 17, 160. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, R. The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open Biol. 2016, 6, 150272. [Google Scholar] [CrossRef] [Green Version]
- Gusarova, V.; Alexa, C.A.; Na, E.; Stevis, P.E.; Xin, Y.; Bonner-Weir, S.; Cohen, J.C.; Hobbs, H.H.; Murphy, A.J.; Yancopoulos, G.D.; et al. ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell 2014, 159, 691–696. [Google Scholar] [CrossRef] [Green Version]
- Abu-Farha, M.; Abubaker, J.; Al-Khairi, I.; Cherian, P.; Noronha, F.; Kavalakatt, S.; Khadir, A.; Behbehani, K.; Alarouj, M.; Bennakhi, A.; et al. Circulating angiopoietin-like protein 8 (betatrophin) association with HsCRP and metabolic syndrome. Cardiovasc. Diabetol. 2016, 15, 25. [Google Scholar] [CrossRef] [Green Version]
- Horn, P.; Metzing, U.B.; Steidl, R.; Romeike, B.; Rauchfuß, F.; Sponholz, C.; Thomas-Rüddel, D.; Ludewig, K.; Birkenfeld, A.L.; Settmacher, U.; et al. Chemerin in peritoneal sepsis and its associations with glucose metabolism and prognosis: A translational cross-sectional study. Crit. Care 2016, 20, 39. [Google Scholar] [CrossRef] [Green Version]
- Gómez-Ambrosi, J.; Pascual, E.; Catalán, V.; Rodríguez, A.; Ramírez, B.; Silva, C.; Gil, M.J.; Salvador, J.; Frühbeck, G. Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J. Clin. Endocrinol. Metab. 2014, 99, E2004-9. [Google Scholar] [CrossRef] [Green Version]
- Fu, Z.; Berhane, F.; Fite, A.; Seyoum, B.; Abou-Samra, A.B.; Zhang, R. Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Sci. Rep. 2014, 4, 5013. [Google Scholar] [CrossRef]
- Reinhart, K.; Brunkhorst, F.M.; Bone, H.-G.; Bardutzky, J.; Dempfle, C.-E.; Forst, H.; Gastmeier, P.; Gerlach, H.; Gründling, M.; John, S.; et al. Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)). Ger. Med. Sci. 2010, 8, Doc14. [Google Scholar] [CrossRef]
- Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002, 106, 3143–3421. [CrossRef]
- Diagnosis and classification of diabetes mellitus. Diabetes Care 2010, 33 (Suppl. S1), S62–S69. [CrossRef] [PubMed] [Green Version]
- Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; de Backer, G.G.; Delgado, V.; Ference, B.A.; et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur. Heart J. 2020, 41, 111–188. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yuan, Y.; Wu, W.; Sun, S.; Zhang, Y.; Chen, Z. PCSK9: A Potential Therapeutic Target for Sepsis. J. Immunol. Res. 2020, 2020, 2687692. [Google Scholar] [CrossRef]
- Walley, K.R.; Boyd, J.H.; Kong, H.J.; Russell, J.A. Low Low-Density Lipoprotein Levels Are Associated with, But Do Not Causally Contribute to, Increased Mortality in Sepsis. Crit. Care Med. 2019, 47, 463–466. [Google Scholar] [CrossRef]
- Winkler, M.S.; Nierhaus, A.; Poppe, A.; Greiwe, G.; Gräler, M.H.; Daum, G. Sphingosine-1-Phosphate: A Potential Biomarker and Therapeutic Target for Endothelial Dysfunction and Sepsis? Shock 2017, 47, 666–672. [Google Scholar] [CrossRef]
- Winkler, M.S.; Märtz, K.B.; Nierhaus, A.; Daum, G.; Schwedhelm, E.; Kluge, S.; Gräler, M.H. Loss of sphingosine 1-phosphate (S1P) in septic shock is predominantly caused by decreased levels of high-density lipoproteins (HDL). J. Intensive Care 2019, 7, 23. [Google Scholar] [CrossRef] [Green Version]
- Guo, C.; Wang, C.; Deng, X.; He, J.; Yang, L.; Yuan, G. ANGPTL8 in metabolic homeostasis: More friend than foe? Open Biol. 2021, 11, 210106. [Google Scholar] [CrossRef]
- Espes, D.; Lau, J.; Carlsson, P.-O. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia 2014, 57, 50–53. [Google Scholar] [CrossRef]
- Fenzl, A.; Itariu, B.K.; Kosi, L.; Fritzer-Szekeres, M.; Kautzky-Willer, A.; Stulnig, T.M.; Kiefer, F.W. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia 2014, 57, 1204–1208. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Yuan, Y.; Hu, L.; Tang, J.; Meng, Z.; Dai, L.; Gao, Y.; Ma, S.; Wang, X.; Yuan, Y.; et al. ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways. J. Adv. Res. 2022. [Google Scholar] [CrossRef] [PubMed]
- Singh, A.; Choubey, M.; Bora, P.; Krishna, A. Adiponectin and Chemerin: Contrary Adipokines in Regulating Reproduction and Metabolic Disorders. Reprod. Sci. 2018, 25, 1462–1473. [Google Scholar] [CrossRef] [PubMed]
- Chan, C.M.; Mitchell, A.L.; Shorr, A.F. Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis*. Crit. Care Med. 2012, 40, 2945–2953. [Google Scholar] [CrossRef] [PubMed]
- Yasuda, Y.; Fukushima, Y.; Kaneki, M.; Martyn, J.A.J. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats. Biochem. Biophys. Res. Commun. 2013, 431, 81–85. [Google Scholar] [CrossRef] [PubMed]
Variable | Control | Insulin Resistance | Sepsis | p-Value |
---|---|---|---|---|
Group (% male) | 18 (33) | 32 (69) | 16 (56) | 0.053 * |
Age [a] | 56 ± 11 | 65 ± 7 | 70 ± 9 | <0.001 |
BMI [kg/m2] | 24.9 ± 4.1 | 28.4 ± 4.4 | 29.1 ± 4.4 | 0.007 |
HOMA-IR [AU] | 1.5 ± 1.0 | 4.1 ± 5.1 | 4.3 ± 4.8 | 0.080 |
Fasting Glucose [mmol/L] | 5.2 ± 0.4 | 7.6 ± 2.5 | 5.8 ± 1.8 | <0.001 |
HbA1c [%] | 5.5 ± 0.4 | 7.0 ± 1.7 | 5.9 ± 1.1 | <0.001 |
HDL [mmol/L] | 1.5 ± 0.46 | 1.13 ± 0.3 | 0.47 ± 0.88 | <0.001 |
LDL [mmol/L] | 3.25 ± 0.90 | 3.41 ± 1.15 | 0.74 ± 0.57 | <0.001 |
TC [mmol/L] | 5.06 ± 0.98 | 5.09 ± 1.27 | 2.35 ± 0.85 | <0.001 |
TAG [mmol/L] | 1.48 ± 1.09 | 2.13 ± 0.88 | 2.21 ± 1.01 | 0.003 |
ALAT [mU/L] | 0.56 ± 0.17 | 0.64 ± 0.29 | 0.88 ± 0.73 | 0.695 |
GGT [mU/L] | 0.90 ± 0.62 | 1.61 ± 2.56 | 2.71 ± 2.41 | 0.047 |
CRP [mg/dL] | 3.8 ± 2.5 | 12.4 ± 32.3 | 221.2 ± 99.6 | <0.001 |
Leukocytes [Gpt/mL] | 6.0 ± 1.5 | 7.1 ± 1.9 | 16.0 ± 6.1 | <0.001 |
Platelets [Gpt/mL] | 236 ± 68 | 256 ± 71 | 330 ± 176 | 0.175 |
Thromboplastine time [%] | 109 ± 11 | 101 ± 17 | 76 ± 10 | <0.001 |
Creatinine [mmol/L] | 67 ± 11 | 89 ± 25 | 189 ± 116 | <0.001 |
Lipid lowering drugs [%] | 0 | 16 | 6 | - |
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Horn, P.; Radtke, S.; Metzing, U.B.; Steidl, R.; Sponholz, C.; Sommerfeld, O.; Roth, J.; Claus, R.A.; Birkenfeld, A.L.; Settmacher, U.; et al. Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis. Biomedicines 2022, 10, 3151. https://doi.org/10.3390/biomedicines10123151
Horn P, Radtke S, Metzing UB, Steidl R, Sponholz C, Sommerfeld O, Roth J, Claus RA, Birkenfeld AL, Settmacher U, et al. Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis. Biomedicines. 2022; 10(12):3151. https://doi.org/10.3390/biomedicines10123151
Chicago/Turabian StyleHorn, Paul, Sascha Radtke, Uta Barbara Metzing, Ricardo Steidl, Christoph Sponholz, Oliver Sommerfeld, Johannes Roth, Ralf A. Claus, Andreas L. Birkenfeld, Utz Settmacher, and et al. 2022. "Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis" Biomedicines 10, no. 12: 3151. https://doi.org/10.3390/biomedicines10123151
APA StyleHorn, P., Radtke, S., Metzing, U. B., Steidl, R., Sponholz, C., Sommerfeld, O., Roth, J., Claus, R. A., Birkenfeld, A. L., Settmacher, U., Rauchfuß, F., & von Loeffelholz, C. (2022). Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis. Biomedicines, 10(12), 3151. https://doi.org/10.3390/biomedicines10123151