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To the Editor:

We read with great interest the article by Garcia-Ruiz et al.,1 a study which evaluated the effects of rosiglitazone on liver histology and mitochondrial function in ob/ob mice, a model of nonalcoholic fatty liver disease (NAFLD). Briefly, in this controlled study, ob/ob mice were treated at 6 weeks of age with 1 mg/kg/day rosiglitazone by mouth for 12 weeks. Garcia-Ruiz et al. evaluated the effects of rosiglitazone on liver histology and mitochondrial function in the model. They revealed that rosiglitazone treatment improved neither the NAFLD inflammatory activity nor the mitochondrial injury of the model. On the contrary, the drug increased liver steatosis, particularly microvesicular steatosis and oxidative stress compared to control groups.

To the best of our knowledge, we presented the first data concerning the effects of rosiglitazone on a nonalcoholic steatohepatitis (NASH) model induced by methionine-choline deficient diet (MCDD).2, 3 We examined the effects of 4 mg/kg/day rosiglitazone given by gavage on histological characteristics of liver in male Wistar rats at 4 and 12 weeks after commencing of feeding either with MCDD or MCDD supplied with methionine and choline (Harlan Teklad Biomedicals, Madison, WI). For grading and staging the histological lesions, the modification system of Brunt et al. was used.4

All MCDD-fed rats exhibited characteristics of NASH with histological evidence of both significant hepatic steatosis and inflammation. In both study periods, MCDD alone led to grade III liver steatosis, irrespective of rosiglitazone use. Rosiglitazone treatment did not change MCDD-induced liver steatosis in either study terms. The rosiglitazone treatment reduced the number of median inflammatory foci and total inflammatory cells in the MCDD + rosiglitazone group as compared to the MCDD group. Rosiglitazone therapy decreased the liver inflammation on the MCDD-induced NASH model with overt inflammation in both study terms.2, 3

As shown in Garcia-Ruiz et al., we also observed that rosiglitazone appeared to have increased the liver malondialdehyde, luminol, and lucigenin levels; however, these differences were not statistically significant in our studies.2, 3 After cytokine tests, we observed that rosiglitazone also improved interleukin-6 levels in the 4-week study and interleukin-1β, interleukin-6, and tumor necrosis factor-α levels in the 12-week study (P < 0.01).3

Our data are the first to show the anti-inflammatory effects of rosiglitazone in NASH. We speculated that rosiglitazone's effect on cytokines may be a key mechanism of its anti-inflammatory effect in NASH.

Different NAFLD models may have different responses in terms of severity. Young ob/ob mice have been known to have fatty livers without overt histological or biological evidence of hepatic inflammation (that is, steatohepatitis).5 Obese ob/ob mice with fatty liver and obvious steatohepatitis have been developed when challenged with lipopolysaccharide endotoxin,6 ischemia-reperfusion, or ethanol.7 Because we used an overt NASH model, we might have observed an anti-inflammatory role of rosiglitazone. Differences between our results and that of Garcia-Ruiz et al. may also be due to the different pathogenetic pathways of the NAFLD models.

References

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  • 1
    Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T, Martinez MA, Munoz-Yague T, Solis-Herruzo JA. Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice. HEPATOLOGY 2007; 46: 414423.
  • 2
    Tahan V, Eren F, Yavuz D, Emekli E, Yuksel M, Goren Z, et al. Rosiglitosone attenuates liver inflammation in a rat model of nonalcoholic steatohepatitis. J Hepatol 2003; 38( Suppl 2): 202.
  • 3
    Tahan V, Eren F, Avsar E, Yavuz D, Yuksel M, Emekli E, et al. Rosiglitazone attenuates liver inflammation in a rat model of nonalcoholic steatohepatitis. Dig Dis Sci 2007. Published online April 10, 2007. Available at: http://www.springerlink.com/content/568006k41n417133. DOI: 10.1007/s10620-007-9756-x.
  • 4
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic seatohepatitis: a proposal for the grading and staging the histological lesions. Am J Gastroenterol 1999; 94: 24672474.
  • 5
    Koteish A, Mae Diehl A. Animal models of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 679690.
  • 6
    Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997; 94: 25572562.
  • 7
    Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 1999; 274: 56925700.

Veysel Tahan*, Nese Imeryuz*, Erol Avsar*, Cigdem Celikel*, Nurdan Tozun*, * Department of Gastroenterology and Pathology Units, Marmara University School of Medicine, Altunizade, Istanbul, Turkey.