IL-33 treatment attenuated diet-induced hepatic steatosis but aggravated hepatic fibrosis - PubMed (original) (raw)
IL-33 treatment attenuated diet-induced hepatic steatosis but aggravated hepatic fibrosis
Yinjie Gao et al. Oncotarget. 2016.
Abstract
The aim of our work was to investigate the role of interleukin-33 (IL-33) and its receptor ST2 in the progression of diet-induced nonalcoholic steatohepatitis (NASH) in mice, and the characteristic expression in livers of patients with NASH. Mice were fed with high-fat diet (HFD) or methionine-choline 4-deficient diet (MCD) and injected intraperitoneally with IL-33. Both mRNA and protein expression levels of IL-33 and ST2 were up-regulated in the livers of mice fed with HFD or MCD. Treatment with IL-33 attenuated diet-induced hepatic steatosis and reduced activities of ALT in serum, as well as ameliorated HFD-induced systemic insulin resistance and glucose intolerance, while aggravated hepatic fibrosis in diet-induced NASH. Furthermore, treatment with IL-33 can also promote Th2 response and M2 macrophage activation and beneficial modulation on expression profiles of fatty acid metabolism genes in livers. ST2 deficiency did not affect hepatic steatosis and fibrosis when fed with controlling diet. IL-33 did not affect diet-induced hepatic steatosis and fibrosis in ST2 knockout mice. Meanwhile, in the livers of patients with NASH, IL-33 was mainly located in hepatic sinusoid, endothelial cells, and hepatic stellate cells. The mRNA expression level of IL-33 and ST2 was elevated with the progression of NASH. In conclusion, treatment with IL-33 attenuated diet-induced hepatic steatosis, but aggravated hepatic fibrosis, in a ST2-dependent manner.
Keywords: Pathology Section; fibrosis; high-fat diet; interleukin-33; methionine-choline-deficient diet; steatosis.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Figure 1. Mice were exposed to HFD for 20 weeks or MCD for 10 weeks to induce NASH
Hepatic IL-33 and ST2 mRNA a., b. and protein expression c. were analyzed by RT-PCR and Western blotting, respectively. IL-33 levels in serum d., e. were analyzed by ELISA method. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus LFD group or control group.
Figure 2. Mice were exposed to HFD for 20 weeks to induce NASH, and injected i.p
twice per week with PBS or recombinant IL-33 (1 μg/injection). Graphs showed weight gain a., blood glucose levels b., hepatic triglyceride c., and serum ALT levels d. in mice. Paraffin-embedded liver sections were stained with hematoxylin-eosin for evaluation of steatohepatitis e.. Mice were fasted for 4 h and received an intraperitoneal injection of insulin (1 U/kg body weight) f. or glucose (2 g/kg body weight) g. for insulin tolerance tests and glucose tolerance tests, respectively. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus LFD group; # p < 0.05 versus HFD group.
Figure 3. Mice were exposed to MCD for 10 weeks to induce NASH, and injected i.p
twice per week with PBS or recombinant IL-33 (1 μg/injection). Graphs showed body weight a., blood glucose levels b., hepatic triglyceride c., and serum ALT levels d. in mice. Paraffin-embedded liver sections were stained with hematoxylin-eosin for evaluation of steatohepatitis e.. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus control group; # p < 0.05 versus MCD group.
Figure 4. Mice were exposed to HFD or MCD, and treated with recombinant IL-33
Paraffin-embedded liver sections were Masson-trichrome-stained for evaluation of fibrosis a.. Graphs showed the fibrosis area b., d. and mRNA levels of Col1A1, α-SMA and TGF-β1 c., e. in livers. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus LFD group or control group; # p < 0.05 versus HFD or MCD group.
Figure 5. Mice were exposed to HFD or MCD, and treated with recombinant IL-33 or PBS
Graphs showed the serum levels of IL-4 a., IL-5 b., and IL-13 c., hepatic protein levels of IL-4 d., IL-5 e., IL-13 f., and IL-12 p70 g., and mRNA levels of IFN-γ h., Arg-1 i., CD206 j., TLR2 k., and iNOS l.. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus PBS-treated group.
Figure 6. Mice were exposed to HFD or MCD, and treated with recombinant IL-33 or PBS
Graphs showed the activity of CPT-I a., and mRNA levels of ACO b., PPARα c., CD36 d., FAS e., SREB-1c f., L-FABP g., MTP h., and ABCA-1 i. in livers. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus PBS-treated group.
Figure 7. ST2 knockout mice and wild-type mice were fed with MCD, and treated with recombinant IL-33 for 10 weeks
Paraffin-embedded liver sections were stained with hematoxylin-eosin for evaluation of steatosis a.. Graphs showed hepatic triglyceride b. and serum ALT levels c. in mice. n = 8-10 in each group. Values are means ± SD; * p < 0.05 versus wild-type mice fed with controlling diet; # p < 0.05 versus wild-type mice fed with MCD diet.
Figure 8. ST2 knockout mice and wild-type mice were fed with HFD, and treated with recombinant IL-33
Paraffin-embedded liver sections were stained with hematoxylin-eosin for evaluation of steatohepatitis a.. Graphs showed hepatic triglyceride b. and serum ALT levels c. in mice. n = 8-10 in each group. Values are means ± SD; # p < 0.05 versus wild-type mice fed with HFD diet.
Figure 9. IL-33 levels in NASH patients
Serum IL-33 levels a. were determined by ELISA method. The mRNA expression of IL-33 b. and ST2 c. was determined by RT-PCR method. Immunohistochemistry analysis of IL-33 d. in livers of NASH patients. HC, healthy control (n = 15); NAFL, non-alcoholic fatty liver (n = 17); borderline-NASH, borderline non-alcoholic steatohepatitis (n = 15); NASH, non-alcoholic steatohepatitis (n = 14). Values are means ± SD; * p < 0.05 versus healthy control.
References
- Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–171. - PubMed
- Cheung O, Sanyal AJ. Recent advances in nonalcoholic fatty liver disease. Curr Opin Gastroenterol. 2010;26:202–208. - PubMed
- Harmon RC, Tiniakos DG, Argo CK. Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5:189–200. - PubMed
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