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Horm Metab Res 2012; 44(12): 885-890
DOI: 10.1055/s-0032-1321819
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Reversion of Steatosis by SREBP-1c Antisense Oligonucleotide did not Improve Hepatic Insulin Action in Diet-induced Obesity Mice

M. F. Vitto
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
G. Luz
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
T. F. Luciano
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
S. O. Marques
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
D. R. Souza
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
R. A. Pinho
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
F. S. Lira
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
,
D. E. Cintra
2   Faculty of Applied Sciences, University of Campinas – UNICAMP, Limeira, SP, Brazil
,
C. T. De Souza
1   Laboratory of Exercise Biochemistry and Physiology, Programa de Pós-Graduação em Ciências da Saúde, Unidade em Ciênicas da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
› Author Affiliations
Further Information

Publication History

received 23 April 2012

accepted 20 June 2012

Publication Date:
29 August 2012 (online)

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Abstract

The literature has associated hepatic insulin action with NAFLD. In this sense, treatments to revert steatosis and improve hepatic insulin action become important. Our group has demonstrated that inhibition of Sterol Regulatory Element Binding Proteins-1c (SREBP-1c) reverses hepatic steatosis. However, insulin signals after NAFLD reversion require better investigation. Thus, in this study, we investigated if the reversal of NAFLD by SREBP-1c inhibitor results in improvement in the hepatic insulin signal in obesity mice. After installation/achievement of diet-induced obesity and insulin resistance, Swiss mice were divided into 3 groups: i) Lean, ii) D-IHS, diet-induced hepatic steatosis [no treatment with antisense oligonucleotide (ASO)], and iii) RD-IHS, reversion of diet-induced hepatic steatosis (treated with ASO). The mice were treated with ASO SREBP-1c as previously described by our group. After ASO treatment, one set of animals was anesthetized and used for in vivo test, and another mice set was anesthetized and used for histology and Western blot analysis. Reversion of diet-induced hepatic steatosis did not change blood glucose, glucose decay constant (kITT), body weight, or serum insulin levels. In addition, results showed that the protocol did not improve insulin pathway signaling, as confirmed by the absence of changes in IR, IRS1, Akt and Foxo1 phosphorylation in hepatic tissue. In parallel, no alterations were observed in proinflammatory molecules. Thus, our results suggest that the inhibition of SREBP-1c reverts steatosis, but without improving insulin hepatic resistance.

Key words

SREBP-1c - steatosis - insulin resistance - inflammation
 

  • References

  • 1 Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008; 28: 339-350
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Ahmed MH, Byrne CD. Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD). Drug Discov Today 2007; 12: 740-747
    CrossrefPubMedSearch in Google Scholar
  • 3 Frederico MJ, Vitto MF, Cesconetto PA, Engelmann J, De Souza DR, Luz G, Pinho RA, Ropelle ER, Cintra DE, De Souza CT. Short-term inhibition of SREBP-1c expression reverses diet-induced non-alcoholic fatty liver disease in mice. Scand J Gastroenterol 2011; 46: 1381-1388
    CrossrefPubMedSearch in Google Scholar
  • 4 Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des 2010; 16: 1941-1951
    CrossrefPubMedSearch in Google Scholar
  • 5 Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995; 16: 117-142
    CrossrefPubMedSearch in Google Scholar
  • 6 Youngren JF. Regulation of insulin receptor function. Cell Mol Life Sci 2007; 64: 873-891
    CrossrefPubMedSearch in Google Scholar
  • 7 MacDonald PE, Joseph JW, Yau D, Diao J, Asghar Z, Dai F, Oudit GY, Patel MM, Backx PH, Wheeler MB. Impaired glucose-stimulated insulin secretion, enhanced intraperitoneal insulin tolerance, and increased beta-cell mass in mice lacking the p110gamma isoform of phosphoinositide 3-kinase. Endocrinology 2004; 145: 4078-483
    CrossrefPubMedSearch in Google Scholar
  • 8 Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci USA 2008; 105: 8292-8297
    CrossrefPubMedSearch in Google Scholar
  • 9 Marchesini G, Moscatiello S, Di Domizio S, Forlani G. Obesity-associated liver disease. J Clin Endocrinol Metab 2008; 93: 74-80
    CrossrefPubMedSearch in Google Scholar
  • 10 Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95: 2409-2415
    CrossrefPubMedSearch in Google Scholar
  • 11 Cai D, Frantz JD, Tawa Jr NE, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 2004; 119: 285-298
    CrossrefPubMedSearch in Google Scholar
  • 12 Ragheb R, Medhat AM, Shanab GM, Seoudi DM, Fantus IG. Links between enhanced fatty acid flux, protein kinase C and NFkappaB activation, and apoB-lipoprotein production in the fructose-fed hamster model of insulin resistance. Biochem Biophys Res Commun 2008; 370: 134-139
    CrossrefPubMedSearch in Google Scholar
  • 13 Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, Corgnati A, Muggeo M. Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies. J Clin Endocrinol Metab 1989; 68: 374-378
    CrossrefPubMedSearch in Google Scholar
  • 14 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
    CrossrefPubMedSearch in Google Scholar
  • 15 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
    CrossrefPubMedSearch in Google Scholar
  • 16 De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005; 146: 4192-4199
    CrossrefPubMedSearch in Google Scholar
  • 17 Barbuio R, Milanski M, Bertolo MB, Saad MJ, Velloso LA. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J Endocrinol 2007; 194: 539-550
    CrossrefPubMedSearch in Google Scholar
  • 18 Marchesini G, Bianchi G. Nonalcoholic fatty liver disease: Disease and comorbidity effects on quality of life. Nat Rev Gastroenterol Hepatol 2009; 6: 504-506
    CrossrefPubMedSearch in Google Scholar
  • 19 Cheung O, Sanyal AJ. Recent advances in nonalcoholic fatty liver disease. Curr Opin Gastroenterol 2010; 26: 202-208
    CrossrefPubMedSearch in Google Scholar
  • 20 Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease. J Biol Chem 2004; 279: 32345-32353
    CrossrefPubMedSearch in Google Scholar
  • 21 Lam TK, Van de Werve G, Giacca A. Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol 2003; 284: 281-290
    PubMedSearch in Google Scholar
  • 22 He XM, Yang QH, Li PF, Chen Z, Feng GF, Wang WJ, Liu HT, Zhang YP, Ji GY. Effect of soothing liver and invigorating spleen recipes on SREBP-1c mRNA and protein expression in hepatic tissues of rats with non-alcoholic fatty liver disease. Zhong Yao Cai 2011; 34: 931-937
    PubMedSearch in Google Scholar
  • 23 Moon YA, Liang G, Xie X, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Brown MS, Goldstein JL, Horton JD. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metab 2012; 15: 240-246
    CrossrefPubMedSearch in Google Scholar
  • 24 Nakatani Y, Kaneto H, Kawamori D, Hatazaki M, Miyatsuka T, Matsuoka TA, Kajimoto Y, Matsuhisa M, Yamasaki Y, Hori M. Modulation of the JNK pathway in liver affects insulin resistance status. J Biol Chem 2004; 279: 45803-45809
    CrossrefPubMedSearch in Google Scholar
  • 25 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91
    CrossrefPubMedSearch in Google Scholar
  • 26 Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase C epsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 2007; 117: 739-745
    CrossrefPubMedSearch in Google Scholar
  • 27 Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333-336
    CrossrefPubMedSearch in Google Scholar
  • 28 Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11: 191-198
    CrossrefPubMedSearch in Google Scholar
  • 29 Jiang S, Messina JL. Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes. Am J Physiol 2011; 301: 454-463
    PubMedSearch in Google Scholar
  • 30 Turner JJ, Foxwell KM, Kanji R, Brenner C, Wood S, Foxwell BM, Feldmann M. Investigation of nuclear factor-κB inhibitors and interleukin-10 as regulators of inflammatory signalling in human adipocytes. Clin Exp Immunol 2010; 162: 487-493
    CrossrefPubMedSearch in Google Scholar
  • 31 Lira FS, Rosa JC, Pimentel GD, Seelaender M, Damaso AR, Oyama LM, do Nascimento CO. Both adiponectin and interleukin-10 inhibit LPS-induced activation of the NF-κB pathway in 3T3-L1 adipocytes. Cytokine 2012; 57: 98-106
    CrossrefPubMedSearch in Google Scholar
  • 32 Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482: 179-185
    PubMedSearch in Google Scholar