Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-κB in mice fed a high-fat diet

Liu,Zhenxiong; Dou,Weijia; Ni,Zhen; Wen,Qinsheng; Zhang,Rong; Qin,Ming; Wang,Xuxia; Tang,Hua; Cao,Ying; Wang,Jingjie; Zhao,Shuguang

doi:10.3892/mmr.2016.5393

Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-κB in mice fed a high-fat diet

Authors:
- Zhenxiong Liu
- Weijia Dou
- Zhen Ni
- Qinsheng Wen
- Rong Zhang
- Ming Qin
- Xuxia Wang
- Hua Tang
- Ying Cao
- Jingjie Wang
- Shuguang Zhao
View Affiliations

Affiliations: Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China, Department of Digestion, General Hospital of Chengdu Military Command, Chengdu, Sichuan 610000, P.R. China, Department of Gastroenterology, Xianyang Hospital of Yan'an University, Xianyang, Shaanxi 712000, P.R. China
Published online on: June 10, 2016 https://doi.org/10.3892/mmr.2016.5393
Pages: 1323-1331

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Insulin resistance (IR) is important in the development and progression of NAFLD. Nuclear erythroid 2‑related factor 2 (Nrf2) has previously been reported to be a novel regulator in NAFLD. The present study determined that Nrf2 knockdown accelerated the onset of obesity and non‑alcoholic steatohepatitis (NASH), via the induction of hepatic IR in mice fed a high‑fat diet (HFD), which was confirmed by an increase in total and hepatic weight in Nrf2‑null‑HFD mice, in addition to marked structural disorder in liver tissues from the Nrf2‑null‑HFD group analyzed by histopathological examination. Subsequently, it was demonstrated that hepatic IR in Nrf2‑null‑HFD mice was influenced by oxidative stress; this was confirmed by an increase in malondialdehyde levels and a decrease in glutathione levels. In addition, it was determined that the induction of hepatic IR by Nrf2 knockdown in HFD-treated mice was regulated by activation of the nuclear factor‑κB (NF‑κB) signaling pathway, as detected by an increase in the expression levels of nuclear NF‑κB, and its downstream effectors interleukin‑6 and tumor necrosis factor‑α. The present study provides insight into the function of Nrf2 in NAFLD, indicating that Nrf2 deletion may lead to hepatic IR by activation of NF‑κB, which is often associated with oxidative stress. Therefore, activation of Nrf2 may limit disease progression and act as a therapeutic approach for the treatment of NASH.

View Figures

View References

1	Musso G, Gambino R, Cassader M and Pagano G: Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 43:617–649. 2011. View Article : Google Scholar
2	Preiss D and Sattar N: Non-alcoholic fatty liver disease: An overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond). 115:141–150. 2008. View Article : Google Scholar
3	Day CP and James OF: Steatohepatitis: A tale of two 'hits'? Gastroenterology. 114:842–845. 1998. View Article : Google Scholar : PubMed/NCBI
4	Musso G, Gambino R and Cassader M: Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 48:1–26. 2009. View Article : Google Scholar
5	Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ and Shulman GI: Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 279:32345–32353. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bugianesi E, Mccullough AJ and Marchesini G: Insulin resistance: A metabolic pathway to chronic liver disease. Hepatology. 42:987–1000. 2005. View Article : Google Scholar : PubMed/NCBI
7	Wellen KE and Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest. 115:1111–1119. 2005. View Article : Google Scholar : PubMed/NCBI
8	Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H and Zick Y: A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem. 272:29911–29918. 1997. View Article : Google Scholar : PubMed/NCBI
9	Houstis N, Rosen ED and Lander ES: Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 440:944–948. 2006. View Article : Google Scholar : PubMed/NCBI
10	Videla LA, Rodrigo R, Araya J and Poniachik J: Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med. 12:555–558. 2006. View Article : Google Scholar : PubMed/NCBI
11	Evans JL, Maddux BA and Goldfine ID: The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal. 7:1040–1052. 2005. View Article : Google Scholar : PubMed/NCBI
12	Zhang DD and Hannink M: Distinct cysteine in Keap1 are required for Keap1-dependent ubiquitination on Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 23:8137–8151. 2003. View Article : Google Scholar : PubMed/NCBI
13	Bataille AM and Manautou JE: Nrf2: A potential target for new therapeutics in liver disease. Clin Pharmacol Ther. 92:340–348. 2012. View Article : Google Scholar : PubMed/NCBI
14	Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, et al: An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 236:313–322. 1997. View Article : Google Scholar : PubMed/NCBI
15	Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T, Dillon JF, Ashford ML and Hayes JD: Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med. 48:357–371. 2010. View Article : Google Scholar
16	Luley C, Ronquist G, Reuter W, Paal V, Gottschling HD, Westphal S, King GL, Bakker SJ, Heine RJ and Hattemer A: Point-of-care testing of triglycerides: Evaluation of the Accutrend triglycerides system. Clin Chem. 46:287–291. 2000.PubMed/NCBI
17	Amaral ME, Oliveira HC, Carneiro EM, Delghingaro-Augusto V, Vieira EC, Berti JA and Boschero AC: Plasma glucose regulation and insulin secretion in hypertriglyceridemic mice. Horm Metab Res. 34:21–26. 2002. View Article : Google Scholar : PubMed/NCBI
18	Angel MF, Ramasastry SS, Swartz WM, Narayanan K, Kuhns DB, Basford RE and Futrell JW: The critical relationship between free radicals and degrees of ischemia: Evidence for tissue intolerance of marginal perfusion. Plast Reconstr Surg. 81:233–239. 1988. View Article : Google Scholar : PubMed/NCBI
19	Zhong D, Zhang Y, Zeng YJ, Gao M, Wu GZ, Hu CJ, Huang G and He FT: MicroRNA-613 represses lipogenesis in HepG2 cells by downregulating LXRα. Lipids Health Dis. 12:322013. View Article : Google Scholar
20	He L, Wang H, Jin H, Guo C, Xie H, Yan K, Li X, Shen Q, Qiao T, Chen G, et al: CIAPIN1 inhibits the growth and proliferation of clear cell renal cell carcinoma. Cancer Lett. 276:88–94. 2009. View Article : Google Scholar
21	Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J and Karin M: IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med. 11:191–198. 2005. View Article : Google Scholar : PubMed/NCBI
22	Nakamuta M, Kohjima M, Morizono S, Kotoh K, Yoshimoto T, Miyagi I and Enjoji M: Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med. 16:631–635. 2005.PubMed/NCBI
23	Mantena SK, King AL, Andringa KK, Eccleston HB and Bailey SM: Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med. 44:1259–1272. 2008. View Article : Google Scholar : PubMed/NCBI
24	Kobayashi M and Yamamoto M: Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. 46:113–140. 2006. View Article : Google Scholar : PubMed/NCBI
25	Liu M, Grigoryev DN, Crow MT, Haas M, Yamamoto M, Reddy SP and Rabb H: Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int. 76:277–285. 2009. View Article : Google Scholar : PubMed/NCBI
26	Chan K, Lu R, Chang JC and Kan YW: NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA. 93:13943–13948. 1996. View Article : Google Scholar : PubMed/NCBI
27	Okada K, Warabi E, Sugimoto H, Horie M, Gotoh N, Tokushige K, Hashimoto E, Utsunomiya H, Takahashi H, Ishii T, et al: Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J Gastroenterol. 48:620–632. 2013. View Article : Google Scholar
28	Sugimoto H, Okada K, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, Yanagawa T, Nakahara A, Hyodo I, et al: Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 298:G283–G294. 2010. View Article : Google Scholar
29	Marchesini G and Forlani G: NASH: From liver diseases to metabolic disorders and back to clinical hepatology. Hepatology. 35:497–499. 2002. View Article : Google Scholar : PubMed/NCBI
30	Hebbard L and George J: Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 8:35–44. 2011. View Article : Google Scholar
31	Biddinger SB and Kahn CR: From mice to men: Insights into the insulin resistance syndromes. Annu Rev Physiol. 68:123–158. 2006. View Article : Google Scholar : PubMed/NCBI
32	Tilg H and Moschen AR: Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol Metab. 19:371–379. 2008. View Article : Google Scholar : PubMed/NCBI
33	Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N and Geerts A: Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences. J Hepatol. 47:142–156. 2007. View Article : Google Scholar : PubMed/NCBI
34	Barnes PJ and Karin M: Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 336:1066–1071. 1997. View Article : Google Scholar : PubMed/NCBI
35	Baker RG, Hayden MS and Ghosh S: NF-κB, inflammation, and metabolic disease. Cell Metab. 13:11–22. 2011. View Article : Google Scholar : PubMed/NCBI
36	Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J and Shoelson SE: Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 11:183–190. 2005. View Article : Google Scholar : PubMed/NCBI
37	Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 132:344–362. 2008. View Article : Google Scholar : PubMed/NCBI