Candesartan, an angiotensin-II receptor blocker, ameliorates insulin resistance and hepatosteatosis by reducing intracellular calcium overload and lipid accumulation
1
조회
0
다운로드
1
인용
0
참고문헌
초록
Insulin resistance is a major contributor to the pathogenesis of several human diseases, including type 2 diabetes, hypertension, and hyperlipidemia. Notably, insulin resistance and hypertension share common abnormalities, including increased oxidative stress, inflammation, and organelle dysfunction. Recently, we showed that excess intracellular Ca2+, a known pathogenic factor in hypertension, acts as a critical negative regulator of insulin signaling by forming Ca2+-phosphoinositides that prevent the membrane localization of AKT, a key serine/threonine kinase signaling molecule. Whether preventing intracellular Ca2+ overload improves insulin sensitivity, however, has not yet been investigated. Here, we show that the antihypertensive agent candesartan, compared with other angiotensin-II receptor blockers, has previously unrecognized beneficial effects on attenuating insulin resistance. We found that candesartan markedly reduced palmitic acid (PA)-induced intracellular Ca2+ overload and lipid accumulation by normalizing dysregulated store-operated channel (SOC)-mediated Ca2+ entry into cells, which alleviated PA-induced insulin resistance by promoting insulin-stimulated AKT membrane localization and increased the phosphorylation of AKT and its downstream substrates. As pharmacological approaches to attenuate intracellular Ca2+ overload in vivo, administering candesartan to obese mice successfully decreased insulin resistance, hepatic steatosis, dyslipidemia, and tissue inflammation by inhibiting dysregulated SOC-mediated Ca2+ entry and ectopic lipid accumulation. The resulting alterations in the phosphorylation of key signaling molecules consequently alleviate impaired insulin signaling by increasing the postprandial membrane localization and phosphorylation of AKT. Thus, our findings provide robust evidence for the pleiotropic contribution of intracellular Ca2+ overload in the pathogenesis of insulin resistance and suggest that there are viable approved drugs that can be repurposed for the treatment of insulin resistance and hypertension.
Abstract
Insulin resistance is a major contributor to the pathogenesis of several human diseases, including type 2 diabetes, hypertension, and hyperlipidemia. Notably, insulin resistance and hypertension share common abnormalities, including increased oxidative stress, inflammation, and organelle dysfunction. Recently, we showed that excess intracellular Ca2+, a known pathogenic factor in hypertension, acts as a critical negative regulator of insulin signaling by forming Ca2+-phosphoinositides that prevent the membrane localization of AKT, a key serine/threonine kinase signaling molecule. Whether preventing intracellular Ca2+ overload improves insulin sensitivity, however, has not yet been investigated. Here, we show that the antihypertensive agent candesartan, compared with other angiotensin-II receptor blockers, has previously unrecognized beneficial effects on attenuating insulin resistance. We found that candesartan markedly reduced palmitic acid (PA)-induced intracellular Ca2+ overload and lipid accumulation by normalizing dysregulated store-operated channel (SOC)-mediated Ca2+ entry into cells, which alleviated PA-induced insulin resistance by promoting insulin-stimulated AKT membrane localization and increased the phosphorylation of AKT and its downstream substrates. As pharmacological approaches to attenuate intracellular Ca2+ overload in vivo, administering candesartan to obese mice successfully decreased insulin resistance, hepatic steatosis, dyslipidemia, and tissue inflammation by inhibiting dysregulated SOC-mediated Ca2+ entry and ectopic lipid accumulation. The resulting alterations in the phosphorylation of key signaling molecules consequently alleviate impaired insulin signaling by increasing the postprandial membrane localization and phosphorylation of AKT. Thus, our findings provide robust evidence for the pleiotropic contribution of intracellular Ca2+ overload in the pathogenesis of insulin resistance and suggest that there are viable approved drugs that can be repurposed for the treatment of insulin resistance and hypertension.
참고문헌 (61)
- Kahn, S. E., "Mechanisms linking obesity to insulin resistance and type 2 diabetes", Nature, 444, pp.840~846 (2006)
- Samuel, V. T., "Mechanisms for insulin resistance: common threads and missing links", Cell, 148, pp.852~871 (2012)
- Taniguchi, C. M., "Critical nodes in signalling pathways : insights into insulin action", Nat. Rev. Mol. Cell Biol, 7, pp.85~96 (2006)
- Catherine Hall, "Insulin receptor endocytosis in the pathophysiology of insulin resistance", Experimental and Molecular Medicine, 52, pp.1~10 (2020), 생화학분자생물학회[DOI]
- Muoio, D. M., "Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes", Nat Rev. Mol. Cell Biol, 9, pp.193~205 (2008)
- 노은, "Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism", Experimental and Molecular Medicine, 48, pp.1~12 (2016), 생화학분자생물학회
- Park, K., "Oxidative Stress and Insulin Resistance : The Coronary Artery Risk Development in Young Adults study", Diabetes Care, 32, pp.1302~1307 (2009)
- Shoelson, S. E., "Inflammation and insulin resistance", J. Clin. Investig, 116, pp.1793~1801 (2006)
- Arruda, A. P., "Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes", Cell Metab, 22, pp.381~397 (2015)
- Flamment, M., "New insights into ER stressinduced insulin resistance", Trends Endocrinol. Metab, 23, pp.381~390 (2012)
- Sangwung, P., "Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications: Potential Role of Alterations in Mitochondrial Function in the Pathogenesis of Insulin Resistance and Type 2 Diabetes", Endocrinology, 161, pp.bqaa017~ (2020)
- Nan Jinyan, "SENP2 regulates mitochondrial function and insulin secretion in pancreatic β cells", Experimental and Molecular Medicine, 54, pp.1~9 (2022), 생화학분자생물학회[DOI]
- Park, H. W., "Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies", Autophagy, 10, pp.2385~2386 (2014)
- Standley, P. R., "Increased platelet cytosolic calcium responses to low density lipoprotein in type II diabetes with and without hypertension", Am. J. Hypertens, 6, pp.938~943 (1993)
- Kang, J. K., "Increased intracellular Ca2+ concentrations prevent membrane localization of PH domains through the formation of Ca2+-phosphoinositides", Proc. Natl. Acad. Sci. U S A, 114, pp.11926~11931 (2017)
- Ginsberg, H. N, "Insulin resistance and cardiovascular disease", J. Clin. Investig, 106, pp.453~458 (2000)
- Ormazabal, V., "Association between insulin resistance and the development of cardiovascular disease", Cardiovasc. Diabetol, 17, pp.122~ (2018)
- Reaven, G. M., "Hypertension and Associated Metabolic Abnormalities — The Role of Insulin Resistance and the Sympathoadrenal System", N. Engl. J. Med, 334, pp.374~382 (1996)
- Dridi, H., "Intracellular calcium leak in heart failure and atrial fibrillation : a unifying mechanism and therapeutic target", Nat. Rev. Cardiol, 17, pp.732~747 (2020)
- Xu, G., "Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers", Diabetes, 61, pp.848~856 (2012)
- Ovalle, F., "Verapamil and beta cell function in adults with recent-onset type 1diabetes", Nat. Med, 24, pp.1108~1112 (2018)
- Xu, G., "Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes", Nat. Commun, 13, pp.1159~ (2022)
- Zaman, M. A., "Drugs targeting the renin-angiotensinaldosterone system", Nat. Rev. Drug. Discov, 1, pp.621~636 (2002)
- Lindholm, L. H., "Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study", J. Hypertens, 20, pp.1879~1886 (2002)
- Haller, H., "Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes", N. Engl. J. Med, 364, pp.907~917 (2011)
- Bryant, C. E., "Effects of losartan and enalapril on serum uric acid and GFR in children with proteinuria", Pediatr. Nephrol, 36, pp.3211~3219 (2021)
- Henriksen, E. J., "The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle", Mol. Cell. Endocrinol, 378, pp.15~22 (2013)
- Rizos, C. V., "Antihypertensive drugs and glucose metabolism", World J. Cardiol, 6, pp.517~530 (2014)
- Henriksen, E. J., "Improvement of insulin sensitivity by antagonism of the reninangiotensin system", Am. J. Physiol. Regul. Integr. Comp. Physiol, 293, pp.R974~R980 (2007)
- Godoy-Lugo, J. A., "Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulinresistant OLETF rats", Endocrine, 75, pp.92~107 (2022)
- Nazarzadeh, M., "Blood pressure lowering and risk of new-onset type 2diabetes : an individual participant data meta-analysis", Lancet, 398, pp.1803~1810 (2021)
- Bokhari, S., "Effects of Angiotensin II Type 1 Receptor Blockade on β-Cell Function in Humans", Diabetes Care, 30, pp.181~181 (2007)
- Scheen, A. J., "Prevention of type 2 diabetes mellitus through inhibition of the Renin-Angiotensin system", Drugs, 64, pp.2537~2565 (2004)
- Benoit, S. C., "Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents", J. Clin. Investig, 119, pp.2577~2589 (2009)
- Kim, O. -H., "Externalized phosphatidylinositides on apoptotic cells are eat-me signals recognized by CD14", Cell Death Differ, 29, pp.1423~1432 (2022)
- Mootha, V. K., "PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes", Nat. Genet, 34, pp.267~273 (2003)
- Subramanian, A., "Gene set enrichment analysis : a knowledge-based approach for interpreting genome-wide expression profiles", Proc. Natl. Acad. Sci. U S A, 102, pp.15545~15550 (2005)
- de Hoon, M. J., "Open source clustering software", Bioinformatics(Oxf, Engl), 20, pp.1453~1454 (2004)
- Yang, X., "Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance", Nature, 451, pp.964~969 (2008)
- Mîinea, C. P., "AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain", Biochem. J, 391, pp.87~93 (2005)
- Patterson, R. L., "Store-Operated Ca2+ Entry: Evidence for a Secretion-like Coupling Model", Cell, 98, pp.487~499 (1999)
- Cahalan, M. D., "STIMulating store-operated Ca2+ entry", Nat. Cell Biol, 11, pp.669~677 (2009)
- Seidler, N. W., "Cyclopiazonic Acid is a Specific Inhibitor of the Ca2+-ATPase of Sarcoplasmic Reticulum*", J. Biol. Chem, 264, pp.17816~17823 (1989)
- Prakriya M., "Curr. Top. Membr" (2013), Academic Press
- Cheng K. T., "Curr. Top. Membr" (2013), Academic Press
- Li, T., "Pathophysiological role of calcium channels and transporters in the multiple myeloma", Cell Commun. Signal, 19, pp.99~ (2021)
- Bortolozzi, M., "The Novel PMCA2 Pump Mutation Tommy Impairs Cytosolic Calcium Clearance in Hair Cells and Links to Deafness in Mice*", J. Biol. Chem, 285, pp.37693~37703 (2010)
- Fu, S., "Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity", Nature, 473, pp.528~531 (2011)
- Glatz, J. F. C., "CD36 (SR-B2) as master regulator of cellular fatty acid homeostasis", Curr. Opin. Lipidol, 33, pp.103~111 (2022)
- Guilherme, A., "Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes", Nat. Rev. Mol. Cell Biol, 9, pp.367~377 (2008)
- Sun, G., "Altered Calcium Homeostasis Is Correlated With Abnormalities of Fasting Serum Glucose, Insulin Resistance, and β-Cell Function in the Newfoundland Population", Diabetes, 54, pp.3336~3339 (2005)
- Lebeche, D., "Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy", Nat. Clin. Pract. Cardiovasc. Med, 5, pp.715~724 (2008)
- Zhang, H., "Structural insights into ligand recognition and activation of angiotensin receptors", Trends Pharmacol. Sci, 42, pp.577~587 (2021)
- Ong, H. L., "The dynamic complexity of the TRPC1 channelosome", Channels (Austin, Tex), 5, pp.424~431 (2011)
- Bosanac, I., "Structure of the inositol 1, 4, 5-trisphosphate receptor binding core in complex with its ligand", Nature, 420, pp.696~700 (2002)
- Shah, R. D., "The antidiabetic agent rosiglitazone upregulates SERCA2 and enhances TNF-alpha-and LPS-induced NF-kappaB-dependent transcription and TNF-alpha-induced IL-6 secretion in ventricular myocytes", Cell. Physiol. Biochem, 15, pp.41~50 (2005)
- Berridge, M. J., "Calcium–a life and death signal", Nature, 395, pp.645~648 (1998)
- Brunet, A., "Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor", Cell, 96, pp.857~868 (1999)
- Yan, W. H., "Candesartan cilexetil prevents diet-induced insulin resistance via peroxisome proliferator-activated receptor-γ activation in an obese rat model", Exp. Ther. Med, 12, pp.272~278 (2016)
- Furuhashi, M., "Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension", Hypertension, 42, pp.76~81 (2003)
- Romero, C. A., "Novel RAAS agonists and antagonists : clinical applications and controversies", Nat. Rev. Endocrinol, 11, pp.242~252 (2015)