The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice

  • Kim, Kyung Eun (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Kim, Hwajin (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Heo, Rok Won (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Shi, Hyun Joo (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Yi, Chin-ok (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Lee, Dong Hoon (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Kim, Hyun Joon (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Kang, Sang Soo (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Cho, Gyeong Jae (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Choi, Wan Sung (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine) ;
  • Roh, Gu Seob (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine)
  • Received : 2015.04.10
  • Accepted : 2015.05.31
  • Published : 2015.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Sirtuin 1 (SIRT1) is a mammalian $NAD^+$-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-${\kappa}B$), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (${\alpha}$-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

Keywords

References

  1. Li X. SIRT1 and energy metabolism. Acta Biochim Biophys Sin (Shanghai). 2013;45:51-60. https://doi.org/10.1093/abbs/gms108
  2. Smith JS, Brachmann CB, Celic I, Kenna MA, Muhammad S, Starai VJ, Avalos JL, Escalante-Semerena JC, Grubmeyer C, Wolberger C, Boeke JD. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc Natl Acad Sci U S A. 2000;97:6658-6663. https://doi.org/10.1073/pnas.97.12.6658
  3. Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012;13:225-238. https://doi.org/10.1038/nrn3209
  4. Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, Purushotham A, Li X. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol. 2010;30:4712-4721. https://doi.org/10.1128/MCB.00657-10
  5. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23:2369-2380. https://doi.org/10.1038/sj.emboj.7600244
  6. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390-392. https://doi.org/10.1126/science.1099196
  7. Anastasiou D, Krek W. SIRT1: linking adaptive cellular responses to aging-associated changes in organismal physiology. Physiology (Bethesda). 2006;21:404-410. https://doi.org/10.1152/physiol.00031.2006
  8. Cohen DE, Supinski AM, Bonkowski MS, Donmez G, Guarente LP. Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction. Genes Dev. 2009;23:2812-2817. https://doi.org/10.1101/gad.1839209
  9. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009;9:327-338. https://doi.org/10.1016/j.cmet.2009.02.006
  10. Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A. 2007;104:12861-12866. https://doi.org/10.1073/pnas.0702509104
  11. Chawla A. Control of macrophage activation and function by PPARs. Circ Res. 2010;106:1559-1569. https://doi.org/10.1161/CIRCRESAHA.110.216523
  12. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Nagai R, Kadowaki T. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem. 2006;281:26602-26614. https://doi.org/10.1074/jbc.M601284200
  13. Deng XQ, Chen LL, Li NX. The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver Int. 2007;27:708-715. https://doi.org/10.1111/j.1478-3231.2007.01497.x
  14. Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, Oh DY, Lu M, Milne JC, Westphal C, Bandyopadhyay G, Olefsky JM. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010;298:E419-428. https://doi.org/10.1152/ajpendo.00417.2009
  15. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-246. https://doi.org/10.1146/annurev-physiol-021909-135846
  16. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796-1808. https://doi.org/10.1172/JCI200319246
  17. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. 2005;25:552-563. https://doi.org/10.1183/09031936.05.00117504
  18. Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, Kitamura N, Toda K, Kaneko T, Horie Y, Han JY, Kato S, Shimoda M, Oike Y, Tomizawa M, Makino S, Ohkura T, Saito H, Kumagai N, Nagata H, Ishii H, Hibi T. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55:415-424. https://doi.org/10.1136/gut.2005.071118
  19. Itoh M, Kato H, Suganami T, Konuma K, Marumoto Y, Terai S, Sakugawa H, Kanai S, Hamaguchi M, Fukaishi T, Aoe S, Akiyoshi K, Komohara Y, Takeya M9, Sakaida I, Ogawa Y. Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans. PLoS One. 2013;8:e82163. https://doi.org/10.1371/journal.pone.0082163
  20. Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, Flavell RA, Davis RJ. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science. 2013;339:218-222. https://doi.org/10.1126/science.1227568
  21. den Boer M, Voshol PJ, Kuipers F, Havekes LM, Romijn JA. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models. Arterioscler Thromb Vasc Biol. 2004;24:644-649. https://doi.org/10.1161/01.ATV.0000116217.57583.6e
  22. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34:738-744. https://doi.org/10.1053/jhep.2001.28055
  23. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007;117:539-548. https://doi.org/10.1172/JCI30542
  24. Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract. 2013;7:e330-341. https://doi.org/10.1016/j.orcp.2013.05.004
  25. Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest. 2011;121:4477-4490. https://doi.org/10.1172/JCI46243
  26. Svegliati Baroni G, D'Ambrosio L, Ferretti G, Casini A, Di Sario A, Salzano R, Ridolfi F, Saccomanno S, Jezequel AM, Benedetti A. Fibrogenic effect of oxidative stress on rat hepatic stellate cells. Hepatology. 1998;27:720-726. https://doi.org/10.1002/hep.510270313
  27. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177:861-870. https://doi.org/10.1164/rccm.200708-1269OC
  28. Yoshizaki T, Milne JC, Imamura T, Schenk S, Sonoda N, Babendure JL, Lu JC, Smith JJ, Jirousek MR, Olefsky JM. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol. 2009;29:1363-1374. https://doi.org/10.1128/MCB.00705-08
  29. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A. 2008;105:9793-9798. https://doi.org/10.1073/pnas.0802917105
  30. Hah YS, Cheon YH, Lim HS, Cho HY, Park BH, Ka SO, Lee YR, Jeong DW, Kim HO, Han MK, Lee SI. Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-${\kappa}B$ activation. PLoS One. 2014;9:e87733. https://doi.org/10.1371/journal.pone.0087733
  31. Purushotham A, Xu Q, Li X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J. 2012;26:656-667. https://doi.org/10.1096/fj.11-195172
  32. Xu F, Gao Z, Zhang J, Rivera CA, Yin J, Weng J, Ye J. Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/- mice: a role of lipid mobilization and inflammation. Endocrinology. 2010;151:2504-2514. https://doi.org/10.1210/en.2009-1013
  33. Williams EJ, Gaca MD, Brigstock DR, Arthur MJ, Benyon RC. Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells. J Hepatol. 2000;32:754-761. https://doi.org/10.1016/S0168-8278(00)80244-5
  34. Kim S, Jung J, Kim H, Heo RW, Yi CO, Lee JE, Jeon BT, Kim WH, Hahm JR, Roh GS. Exendin-4 improves nonalcoholic fatty liver disease by regulating glucose transporter 4 expression in ob/ob mice. Korean J Physiol Pharmacol. 2014;18:333-339. https://doi.org/10.4196/kjpp.2014.18.4.333
  35. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271:665-668. https://doi.org/10.1126/science.271.5249.665
  36. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280:E745-751. https://doi.org/10.1152/ajpendo.2001.280.5.E745
  37. De Taeye BM, Novitskaya T, McGuinness OP, Gleaves L, Medda M, Covington JW, Vaughan DE. Macrophage TNF-alpha contributes to insulin resistance and hepatic steatosis in diet-induced obesity. Am J Physiol Endocrinol Metab. 2007;293:E713-725. https://doi.org/10.1152/ajpendo.00194.2007
  38. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem. 2000;275:9047-9054. https://doi.org/10.1074/jbc.275.12.9047

Cited by

  1. Targeting endoplasmic reticulum stress in liver disease vol.10, pp.9, 2015, https://doi.org/10.1080/17474124.2016.1179575
  2. The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome vol.74, pp.10, 2015, https://doi.org/10.1007/s00018-016-2431-7
  3. Melatonin Modulation of Sirtuin-1 Attenuates Liver Injury in a Hypercholesterolemic Mouse Model vol.2018, pp.None, 2015, https://doi.org/10.1155/2018/7968452
  4. SIRT1 mediates the role of RNA-binding protein QKI 5 in the synthesis of triglycerides in non-alcoholic fatty liver disease mice via the PPARα/FoxO1 signaling pathway vol.43, pp.3, 2015, https://doi.org/10.3892/ijmm.2019.4059
  5. Role of histone deacetylase on nonalcoholic fatty liver disease vol.15, pp.4, 2015, https://doi.org/10.1080/17474124.2021.1854089