SerpinA3N deficiency attenuates steatosis and enhances insulin signaling in male mice

in Journal of Endocrinology
Authors:
Melanie Tran Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

Search for other papers by Melanie Tran in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0003-1427-841X
,
Golam Mostofa Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

Search for other papers by Golam Mostofa in
Current site
Google Scholar
PubMed Close
,
Michael Picard Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

Search for other papers by Michael Picard in
Current site
Google Scholar
PubMed Close
,
Jianguo Wu Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

Search for other papers by Jianguo Wu in
Current site
Google Scholar
PubMed Close
,
Li Wang Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA

Search for other papers by Li Wang in
Current site
Google Scholar
PubMed Close
, and
Dong-Ju Shin Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

Search for other papers by Dong-Ju Shin in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to M Tran or D-J Shin: metran@uchc.edu or dong-ju-shin@uconn.edu
DOI:
https://doi.org/10.1530/JOE-22-0073
Volume/Issue:
Volume 256: Issue 3
Article Type:
Research Article
Article ID:
e220073
Online Publication Date:
03 Feb 2023
Copyright:
© Society for Endocrinology 2023
Restricted access
Rent on DeepDyve

Sign up for journal news

Aberrant hepatic lipid metabolism is the major cause of non-alcoholic fatty liver disease (NAFLD) and is associated with insulin resistance and type 2 diabetes. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) is highly expressed in the liver; however, its functional role in regulating NAFLD and associated metabolic disorders are not known. Male wildtype and hepatocyte Serpina3N knockout (HKO) mice were fed a control diet, methionine- and choline-deficient diet or high-fat high-sucrose diet to induce NAFLD and markers of lipid metabolism and glucose homeostasis were assessed. SerpinA3N protein was markedly induced in mice with fatty livers. Hepatic deletion of SerpinA3N attenuated steatosis which correlated with altered lipid metabolism genes, increased fatty acid oxidation activity and enhanced insulin signaling in mice with NAFLD. Additionally, SerpinA3N HKO mice had reduced epididymal white adipose tissue mass, leptin, and insulin levels, improved glucose tolerance, and enhanced insulin sensitivity which was associated with elevated insulin-like growth factor binding protein-1 (IGFBP1) and activation of the leptin receptor (LEPR)-STAT3 signaling pathway. Our findings provide a novel insight into the functional role of SerpinA3N in regulating NAFLD and glucose homeostasis.

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 455 221 5
PDF Downloads 258 69 5

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2023
Article ID:
e220073
Article Type:
Research Article
Received Date:
18 Dec 2022
Accepted Date:
10 Jan 2023
Print Publication Date:
01 Mar 2023
Online Publication Date:
03 Feb 2023
Keywords:
fatty liver; glucose metabolism; insulin signaling; leptin; fatty acid oxidation

  • Aslam MS & Yuan L 2020 Serpina3n: potential drug and challenges, mini review. Journal of Drug Targeting 28 368–378. (https://doi.org/10.1080/1061186X.2019.1693576)

  • Bae JH, Song DK & Im SS 2013 Regulation of IGFBP-1 in metabolic diseases. Journal of Lifestyle Medicine 3 73–79.

  • Brown MS & Goldstein JL 2008 Selective versus total insulin resistance: a pathogenic paradox. Cell Metabolism 7 95–96. (https://doi.org/10.1016/j.cmet.2007.12.009)

  • Byrne CD & Targher G 2015 NAFLD: a multisystem disease. Journal of Hepatology 62(Supplement) S47–S64. (https://doi.org/10.1016/j.jhep.2014.12.012)

  • Cao LL, Pei XF, Qiao X, Yu J, Ye H, Xi CL, Wang PY & Gong ZL 2018 SERPINA3 silencing inhibits the migration, invasion, and liver metastasis of colon cancer cells. Digestive Diseases and Sciences 63 2309–2319. (https://doi.org/10.1007/s10620-018-5137-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Choi Y, Choi H, Toon BK, Lee H, Seok JW, Kim HJ & Kim JW 2020 Serpina3c regulates adipogenesis by modulating insulin growth factor 1 and integrin signaling. iScience 23 100961. (https://doi.org/10.1016/j.isci.2020.100961)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cimini FA, Barchetta I, Carotti S, Bertoccini L, Baroni MG, Vespasiani-Gentilucci U, Cavallo MG & Morini S 2017 Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcholic fatty liver disease. World Journal of Gastroenterology 23 3407–3417. (https://doi.org/10.3748/wjg.v23.i19.3407)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J & Lacorte JM et al.1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392 398–401. (https://doi.org/10.1038/32911)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dalby MJ, Aviello G, Ross AW, Walker AW, Barrett P & Morgan PJ 2018 Diet induced obesity is independent of metabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N. Scientific Reports 8 15648. (https://doi.org/10.1038/s41598-018-33928-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • de Luca C, Kowalski TJ, Zhang Y, Elmquist JK, Lee C, Kilimann MW, Ludwig T, Liu SM & Chua SC 2005 Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. Journal of Clinical Investigation 115 3484–3493. (https://doi.org/10.1172/JCI24059)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Duval C, Thissen U, Keshtkar S, Accart B, Steinstra R, Boekschoten MV, Roskams T, Kersten S & Muller M 2010 Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice. Diabetes 59 3181–3191. (https://doi.org/10.2337/db10-0224)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fishman S, Muzumdar RH, Atzmon G, Ma X, Yang X, Einstein FH & Barzilai N 2007 Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. FASEB Journal 21 53–60. (https://doi.org/10.1096/fj.06-6557com)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Friedman SL, Neuschwander-Tetri BA, Rinella M & Sanyal AJ 2018 Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24 908–922. (https://doi.org/10.1038/s41591-018-0104-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gueugneau M, d’Hose D, Barbé C, de Barsy M, Lause P, Maiter D, Bindels LB, Delzenne NM, Schaeffer L & Gangloff YG et al.2018 Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy. Journal of Cachexia, Sarcopenia and Muscle 9 929–946. (https://doi.org/10.1002/jcsm.12315)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hackl MT, Fürnsinn C, Schuh CM, Krssak M, Carli F, Guerra S, Freudenthaler A, Baumgartner-Parzer S, Helbich TH & Luger A et al.2019 Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis. Nature Communications 10 2717. (https://doi.org/10.1038/s41467-019-10684-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Haile Y, Carmine-Simmen K, Olechowski C, Kerr B, Bleackley RC & Giuliani F 2015 Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo. Journal of Neuroinflammation 12 157. (https://doi.org/10.1186/s12974-015-0376-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Haywood NJ, Cordell PA, Tang KY, Makova N, Yuldasheva NY, Imrie H, Viswambharan H, Bruns AF, Cubbon RM & Kearney MT et al.2017 Insulin-like growth factor binding protein 1 could improve glucose regulation and insulin sensitivity through its RGD domain. Diabetes 66 287–299. (https://doi.org/10.2337/db16-0997)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Horiguchi N, Wang L, Mukhopadhyay P, Park O, Jeong WIl, Lafdil F, Osei-Hyiaman D, Moh A, Fy XY & Pacher P et al.2008 Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology 134 1148–1158. (https://doi.org/10.1053/j.gastro.2008.01.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Horvath AJ, Irving JA, Rossjohn J, Law RH, Bottomley SP, Quinsey NS, Pike RN, Couglin PB & Whisstock JC 2005 The murine orthologue of human antichymotrypsin: a structural paradigm for clade A3 serpins. Journal of Biological Chemistry 280 43168–43178. (https://doi.org/10.1074/jbc.M505598200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huynh FK, Levi J, Denroche HC, Gray SL, Voshol PJ, Neumann UH, Speck M, Chua SC, Covey SD & Kieffer TJ 2010 Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. Diabetes 59 3032–3040. (https://doi.org/10.2337/db10-0074)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, Hashimoto N, Kido Y, Mori T & Sakaue H et al.2004 Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nature Medicine 10 168–174. (https://doi.org/10.1038/nm980)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jones JI, Gockerman A, Busby WH, Wright G & Clemmons DR 1993 Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the α5β1 integrin by means of its Arg-Gly-Asp sequence. PNAS 90 10553–10557. (https://doi.org/10.1073/pnas.90.22.10553)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim JK 2009 Hyperinsulinemic-euglycemic clamp to assess insulin sensitivity in vivo. Methods in Molecular Biology 560 221–238. (https://doi.org/10.1007/978-1-59745-448-3_15)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kinoshita S, Ogawa W, Okamoto Y, Takashima M, Inoue H, Matsuki Y, Watanabe E, Hiramatsu R & Kasuga M 2008 Role of hepatic STAT3 in the regulation of lipid metabolism. Kobe Journal of Medical Sciences 54 E200–E208.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ko E, Kim JS, Bae JW, Kim J, Park SG & Jung G 2019 SERPINA3 is a key modulator of HNRNP-K transcriptional activity against oxidative stress in HCC. Redox Biology 24 101217. (https://doi.org/10.1016/j.redox.2019.101217)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kotronen A, Lewitt M, Hall K, Brismar K & Yki-Järvinen H 2008 Insulin-like growth factor binding protein 1 as a novel specific marker of hepatic insulin sensitivity. Journal of Clinical Endocrinology and Metabolism 93 4867–4872. (https://doi.org/10.1210/jc.2008-1245)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kroy DC, Beraza N, Tschaharganeh DF, Sander LE, Erschfeld S, Giebeler A, Liedtke C, Wasmuth HE, Trautwein C & Streetz KL 2010 Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology 51 463–473. (https://doi.org/10.1002/hep.23322)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee Y, Wang MY, Kakuma T, Wang ZW, Babcock E, McCorkle K, Higa M, Zhou YT & Unger RH 2001 Liporegulation in Diet-induced Obesity: the antisteatotic role of hyperleptinemia. Journal of Biological Chemistry 276 5629–5635. (https://doi.org/10.1074/jbc.M008553200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C, Witters LA & Unger RH 2002 PPARα is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. PNAS 99 11848–11853. (https://doi.org/10.1073/pnas.182420899)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lefere S & Tacke F 2019 Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Reports 1 30–43. (https://doi.org/10.1016/j.jhepr.2019.02.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li BY, Guo YY, Xiao G, Guo L & Tang QQ 2022 SERPINA3C ameliorates adipose tissue inflammation through the cathepsin G/integrin/AKT pathway. Molecular Metabolism 61 101500. (https://doi.org/10.1016/j.molmet.2022.101500)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li WC, Ralphs KL & Tosh D 2010 Isolation and culture of adult mouse hepatocytes. Methods in Molecular Biology 633 185–196. (https://doi.org/10.1007/978-1-59745-019-5_13)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martínez-Uña M, Lopez-Mancheno Y, Dieguez C, Fernandez-Rojo MA & Novelle MG 2020 Unraveling the role of leptin in liver function and Its relationship with liver diseases. International Journal of Molecular Sciences 24 9368. (https://doi.org/10.3390/ijms21249368)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN & Hurst JA et al.1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387 903–908. (https://doi.org/10.1038/43185)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Myers MG, Leibel RL, Seeley RJ & Schwartz MW 2010 Obesity and leptin resistance: distinguishing cause from effect. Trends in Endocrinology and Metabolism 21 643–651. (https://doi.org/10.1016/j.tem.2010.08.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Qureshi K & Abrams GA 2007 Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World Journal of Gastroenterology 13 3540–3553. (https://doi.org/10.3748/wjg.v13.i26.3540)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rajkumar K, Modric T & Murphy LJ 1999 Impaired adipogenesis in insulin-like growth factor binding protein-1 transgenic mice. Journal of Endocrinology 162 457–465. (https://doi.org/10.1677/joe.0.1620457)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rajwani A, Ezzat V, Smith J, Yuldasheva NY, Duncan ER, Gage M, Cubbon RM, Kahn MB, Imrie H & Abbas A et al.2012 Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis. Diabetes 61 915–924. (https://doi.org/10.2337/db11-0963)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roglans N, Vilà L, Farré M, Alegret M, Sánchez RM, Vázquez-Carrera M & Laguna JC 2007 Impairment of hepatic STAT-3 activation and reduction of PPARα activity in fructose-fed rats. Hepatology 45 778–788. (https://doi.org/10.1002/hep.21499)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Saltiel AR & Khan CR 2001 Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414 799–806. (https://doi.org/10.1038/414799a)

  • Sergi D, Campbell FM, Grant C, Morris AC, Bachmair EM, Koch C, McLean FH, Muller A, Hoggard N & de Roos B et al.2018 SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. Genes and Nutrition 13 28. (https://doi.org/10.1186/s12263-018-0619-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smith U & Kahn BB 2016 Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. Journal of Internal Medicine 280 465–475. (https://doi.org/10.1111/joim.12540)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tabbi-Anneni I, Cooksey R, Gunda V, Liu S, Mueller A, Song G, McClain DA & Wang L 2010 Overexpression of nuclear receptor SHP in adipose tissues affects diet-induced obesity and adaptive thermogenesis. American Journal of Physiology: Endocrinology and Metabolism 298 E961–E970. (https://doi.org/10.1152/ajpendo.00655.2009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tjondrokoesoemo A, Schips T, Kanisicak O, Sargent MA & Molkentin JD 2016 Genetic overexpression of serpina3n attenuates muscular dystrophy in mice. Human Molecular Genetics 25 1192–1202. (https://doi.org/10.1093/hmg/ddw005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tran M, Lee SM, Shin DJ & Wang L 2017 Loss of miR-141/200c ameliorates hepatic steatosis and inflammation by reprogramming multiple signaling pathways in NASH. JCI Insight 2 e96094. (https://doi.org/10.1172/jci.insight.96094)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tran M, Wu J, Wang L & Shin DJ 2021 A potential role for SerpinA3N in acetaminophen-induced hepatotoxicity. Molecular Pharmacology 99 277–285. (https://doi.org/10.1124/molpharm.120.000117)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vicuña L, Strochlic DE, Latremoliere A, Bali KK, Simonetti M, Husainie D, Prokosch S, Riva P, Griffin RS & Njoo C et al.2015 The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nature Medicine 21 518–523. (https://doi.org/10.1038/nm.3852)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Waise TMZ, Toshinai K, Naznin F, NamKoong C, Md Moin AS, Sakoda H & Nakazato M 2015 One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice. Biochemical and Biophysical Research Communications 464 1157–1162. (https://doi.org/10.1016/j.bbrc.2015.07.097)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wallace TM, Levy JC & Matthews DR 2004 Use and abuse of HOMA modeling. Diabetes Care 27 1487–1495. (https://doi.org/10.2337/diacare.27.6.1487)

  • Wang B, Chandrasekera PC & Pippin JJ 2014 Leptin- and leptin receptor-deficient rodent models: relevance for human Type 2 diabetes. Current Diabetes Reviews 10 131–145. (https://doi.org/10.2174/1573399810666140508121012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J & Yuan Y et al.2018 JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metabolism 27 136–150.e5. (https://doi.org/10.1016/j.cmet.2017.11.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yoshino S, Satoh T, Yamada M, Hashimoto K, Tomaru T, Katano-Toki A, Kakizaki S, Okada S, Shimizu H & Ozawa A et al.2014 Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor. Endocrinology 155 3459–3472. (https://doi.org/10.1210/en.2013-2160)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y, He J, Zhao J, Xu M, Lou D, Tso P, Li Z & Li X 2017 Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes. Biochemical and Biophysical Research Communications 487 327–332. (https://doi.org/10.1016/j.bbrc.2017.04.058)

    • PubMed
    • Search Google Scholar
    • Export Citation