Hepatic nNOS impaired hepatic insulin sensitivity through the activation of p38 MAPK

in Journal of Endocrinology
Authors:
Tianxue Zhao Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

Search for other papers by Tianxue Zhao in
Current site
Google Scholar
PubMed Close
,
Qian Li Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

Search for other papers by Qian Li in
Current site
Google Scholar
PubMed Close
,
Qianyun Mao Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

Search for other papers by Qianyun Mao in
Current site
Google Scholar
PubMed Close
,
Kaida Mu Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

Search for other papers by Kaida Mu in
Current site
Google Scholar
PubMed Close
, and
Chen Wang Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

Search for other papers by Chen Wang in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to C Wang: wangchen@sjtu.edu.cn

*(T Zhao and Q Li contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-20-0322
Volume/Issue:
Volume 248: Issue 3
Article Type:
Research Article
Page Range:
265–275
Online Publication Date:
Mar 2021
Copyright:
© 2021 Society for Endocrinology 2021
Restricted access
Rent on DeepDyve

Sign up for journal news

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRbeta and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRbeta, p-Akt, and p-GSK3beta in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRbeta and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin-signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 1182 24 0
PDF Downloads 694 25 0

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
11
Article Type:
Research Article
Received Date:
26 Nov 2020
Accepted Date:
05 Jan 2021
Print Publication Date:
01 Mar 2021
Online Publication Date:
Mar 2021
Keywords:
neuronal nitric oxide synthase (nNOS); insulin resistance; p38 MAPK; obesity

  • An Z, DiCostanzo CA, Moore MC, Edgerton DS, Dardevet DP, Neal DW & Cherrington AD 2008 Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog. American Journal of Physiology. Endocrinology and Metabolism 294 E300–E 306. (https://doi.org/10.1152/ajpendo.00380.2007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bachar E, Ariav Y, Cerasi E, Kaiser N & Leibowitz G 2010 Neuronal nitric oxide synthase protects the pancreatic beta cell from glucolipotoxicity-induced endoplasmic reticulum stress and apoptosis. Diabetologia 53 2177–2187. (https://doi.org/10.1007/s00125-010-1833-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Baldelli S, LettieriBarbato D, Tatulli G, Aquilano K & Ciriolo MR 2014 The role of nNOS and PGC-1alpha in skeletal muscle cells. Journal of Cell Science 127 4813–4820. (https://doi.org/10.1242/jcs.154229)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Borgs M, Bollen M, Keppens S, Yap SH, Stalmans W & Vanstapel F 1996 Modulation of basal hepatic glycogenolysis by nitric oxide. Hepatology 23 1564–1571. (https://doi.org/10.1002/hep.510230637)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML & Courtney MJ 2005 The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. Journal of Cell Biology 168 117–126. (https://doi.org/10.1083/jcb.200407024)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Carvalho-Filho MA, Ueno M, Hirabara SM, Seabra AB, Carvalheira JB, de Oliveira MG, Velloso LA, Curi R & Saad MJ 2005 S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. Diabetes 54 959–967. (https://doi.org/10.2337/diabetes.54.4.959)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dong K, Li H, Zhang M, Jiang S, Chen S, Zhou J, Dai Z, Fang Q & Jia W 2015 Endoplasmic reticulum stress induces up-regulation of hepatic β-klotho expression through ATF4 signaling pathway. Biochemical & Biophysical Research Communications 459 300–305. (https://doi.org/10.1016/j.bbrc.2015.02.104)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fujimoto M, Shimizu N, Kunii K, Martyn JA, Ueki K & Kaneki M 2005 A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. Diabetes 54 1340–1348. (https://doi.org/10.2337/diabetes.54.5.1340)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gomez-Valades AG, Mendez-Lucas A, Vidal-Alabro A, Blasco FX, Chillon M, Bartrons R, Bermudez J & Perales JC 2008 Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice. Diabetes 57 2199–2210. (https://doi.org/10.2337/db07-1087)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gross B, Pawlak M, Lefebvre P & Staels B 2017 PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nature Reviews. Endocrinology 13 36–49. (https://doi.org/10.1038/nrendo.2016.135)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gum RJ, Gaede LL, Heindel MA, Waring JF, Trevillyan JM, Zinker BA, Stark ME, Wilcox D, Jirousek MR, Rondinone CM. 2003 Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice. Molecular Endocrinology 17 1131–1143. (https://doi.org/10.1210/me.2002-0288)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hemi R, Yochananov Y, Barhod E, Kasher-Meron M, Karasik A, Tirosh A & Kanety H 2011 p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance. Diabetes 60 1134–1145. (https://doi.org/10.2337/db09-1323)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jaffrey SR, Snowman AM, Eliasson MJ, Cohen NA & Snyder SH 1998 CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron 20 115–124. (https://doi.org/10.1016/s0896-6273(0080439-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kajiwara A, Tsuchiya Y, Takata T, Nyunoya M, Nozaki N, Ihara H & Watanabe Y 2013 Nitric oxide enhances increase in cytosolic Ca(2+) and promotes nicotine-triggered MAPK pathway in PC12 cells. Nitric Oxide : Biology and Chemistry 34 3–9. (https://doi.org/10.1016/j.niox.2013.04.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R & Harada N 2007 Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. International Journal of Molecular Medicine 20 351–358. (https://doi.org/10.3892/ijmm.20.3.351)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lai TW, Zhang S & Wang YT 2014 Excitotoxicity and stroke: identifying novel targets for neuroprotection. Progress in Neurobiology 115 157–188. (https://doi.org/10.1016/j.pneurobio.2013.11.006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, Pan X, Bao Y & Xiang K 2010 Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. Journal of Hepatology 53 934–940. (https://doi.org/10.1016/j.jhep.2010.05.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li Q, Zhao Q, Zhang J, Zhou L, Zhang W, Chua B, Chen Y, Xu L & Li P 2019 The protein phosphatase 1 complex is a direct target of AKT that links insulin signaling to hepatic glycogen deposition. Cell Reports 28 3406–3422.e7. (https://doi.org/10.1016/j.celrep.2019.08.066)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Loria P, Lonardo A & Anania F 2013 Liver and diabetes. A vicious circle. Hepatology Research 43 51–64. (https://doi.org/10.1111/j.1872-034X.2012.01031.x)

  • Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, Ahima RS, Ueki K, Kahn CR & Birnbaum MJ 2012 Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and FoxO1. Nature Medicine 18 388–395. (https://doi.org/10.1038/nm.2686)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu XM, Zhao H & Zhang HP 2013 Role of neuronal nitric oxide synthase in the cardiac ischemia reperfusion in mice. Chinese Journal of Physiology 56 291–297. (https://doi.org/10.4077/CJP.2013.BAB143)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marsollier N, Kassis N, Mezghenna K, Soty M, Fioramonti X, Lacombe A, Joly A, Pillot B, Zitoun C & Vilar J 2009 Deregulation of hepatic insulin sensitivity induced by central lipid infusion in rats is mediated by nitric oxide. PLOS ONE 4 e6649. (https://doi.org/10.1371/journal.pone.0006649).

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mezghenna K, Leroy J, Azay-Milhau J, Tousch D, Castex F, Gervais S, Delgado-Betancourt V, Gross R & Lajoix AD 2014 Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats. Diabetologia 57 177–186. (https://doi.org/10.1007/s00125-013-3084-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mezghenna K, Pomies P, Chalancon A, Castex F, Leroy J, Niclauss N, Nadal B, Cambier L, Cazevieille C & Petit P 2011 Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity. Diabetologia 54 2856–2866. (https://doi.org/10.1007/s00125-011-2264-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Millar JS, Stone SJ, Tietge UJ, Tow B, Billheimer JT, Wong JS, Hamilton RL, Farese RV Jr & Rader DJ 2006 Short-term overexpression of DGAT1 or DGAT2 increases hepatic triglyceride but not VLDL triglyceride or apoB production. Journal of Lipid Research 47 2297–2305. (https://doi.org/10.1194/jlr.M600213-JLR200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moran-Salvador E, Lopez-Parra M, Garcia-Alonso V, Titos E, Martinez-Clemente M, Gonzalez-Periz A, Lopez-Vicario C, Barak Y, Arroyo V & Claria J 2011 Role for PPARgamma in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB Journal 25 2538–2550. (https://doi.org/10.1096/fj.10-173716)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mu K, Sun Y, Zhao Y, Zhao T, Li Q, Zhang M, Li H, Zhang R, Hu C & Wang C 2019 Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain. EBiomedicine 47 352–364. (https://doi.org/10.1016/j.ebiom.2019.08.033)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Muniyappa R, Montagnani M, Koh KK & Quon MJ 2007 Cardiovascular actions of insulin. Endocrine Reviews 28 463–491. (https://doi.org/10.1210/er.2007-0006)

  • Nakata S, Tsutsui M, Shimokawa H, Suda O, Morishita T, Shibata K, Yatera Y, Sabanai K, Tanimoto A & Nagasaki M 2008 Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation 117 2211–2223. (https://doi.org/10.1161/CIRCULATIONAHA.107.742692)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • O-Sullivan I, Zhang W, Wasserman DH, Liew CW, Liu J, Paik J, DePinho RA, Stolz DB, Kahn CR & Schwartz MW 2015 FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nature Communications 6 7079. (https://doi.org/10.1038/ncomms8079)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pasarin M, Abraldes JG, Rodriguez-Vilarrupla A, La Mura V, Garcia-Pagan JC & Bosch J 2011 Insulin resistance and liver microcirculation in a rat model of early NAFLD. Journal of Hepatology 55 1095–1102. (https://doi.org/10.1016/j.jhep.2011.01.053)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Petersen MC & Shulman GI 2018 Mechanisms of insulin action and insulin resistance. Physiological Reviews 98 2133–2223. (https://doi.org/10.1152/physrev.00063.2017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pettinelli P & Videla LA 2011 Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. Journal of Clinical Endocrinology and Metabolism 96 1424–1430. (https://doi.org/10.1210/jc.2010-2129)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Qu S, Altomonte J, Perdomo G, He J, Fan Y, Kamagate A, Meseck M & Dong HH 2006 Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 147 5641–5652. (https://doi.org/10.1210/en.2006-0541)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sansbury BE & Hill BG 2014 Regulation of obesity and insulin resistance by nitric oxide. Free Radical Biology & Medicine 73 383–399. (https://doi.org/10.1016/j.freeradbiomed.2014.05.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shankar RR, Wu Y, Shen HQ, Zhu JS & Baron AD 2000 Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes 49 684–687. (https://doi.org/10.2337/diabetes.49.5.684)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sheldon RD, Laughlin MH & Rector RS 2014 Reduced hepatic eNOS phosphorylation is associated with NAFLD and type 2 diabetes progression and is prevented by daily exercise in hyperphagic OLETF rats. Journal of Applied Physiology 116 1156–1164. (https://doi.org/10.1152/japplphysiol.01275.2013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shinozaki S, Choi CS, Shimizu N, Yamada M, Kim M, Zhang T, Shiota G, Dong HH, Kim YB & Kaneki M 2011 Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice. Journal of Biological Chemistry 286 34959–34975. (https://doi.org/10.1074/jbc.M110.187666)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun H, Wang X, Chen J, Song K, Gusdon AM, Li L, Bu L & Qu S 2016 Melatonin improves non-alcoholic fatty liver disease via MAPK-JNK/P38 signaling in high-fat-diet-induced obese mice. Lipids in Health & Disease 15 202. (https://doi.org/10.1186/s12944-016-0370-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, Clowes AW, Morton GJ, Schwartz MW & Kim F 2011 Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding. Diabetes 60 2792–2801. (https://doi.org/10.2337/db11-0255)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang L, Calay ES, Fan J, Arduini A, Kunz RC, Gygi SP, Yalcin A, Fu S & Hotamisligil GS 2015 METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349 500–506. (https://doi.org/10.1126/science.aaa0079)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang W, Sun Q, Zhong W, Sun X & Zhou Z 2016 Hepatic peroxisome proliferator-activated receptor gamma signaling contributes to alcohol-induced hepatic steatosis and inflammation in mice. Alcoholism, Clinical and Experimental Research 40 988–999. (https://doi.org/10.1111/acer.13049)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu LJ, Li TY, Luo CX, Jiang N, Chang L, Lin YH, Zhou HH, Chen C, Zhang Y & Lu W 2014 CAPON-nNOS coupling can serve as a target for developing new anxiolytics. Nature Medicine 20 1050–1054. (https://doi.org/10.1038/nm.3644)

    • PubMed
    • Search Google Scholar
    • Export Citation