Telmisartan attenuates progression of steatohepatitis in mice: role of hepatic macrophage infiltration and effects on adipose tissue
Hiroshi Kudo
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorYutaka Yata
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Saiseikai-Maebashi Hospital, Gunma, Japan
Search for more papers by this authorTerumi Takahara
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorKengo Kawai
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorYasuhiro Nakayama
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorMasami Kanayama
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorTakeshi Oya
Department of Pathology, University of Toyama, Toyama, Japan
Search for more papers by this authorSeiichi Morita
Second Department of Surgery, University of Toyama, Toyama, Japan
Search for more papers by this authorMasakiyo Sasahara
Department of Pathology, University of Toyama, Toyama, Japan
Search for more papers by this authorDerek A. Mann
Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Search for more papers by this authorToshiro Sugiyama
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorHiroshi Kudo
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorYutaka Yata
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Saiseikai-Maebashi Hospital, Gunma, Japan
Search for more papers by this authorTerumi Takahara
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorKengo Kawai
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorYasuhiro Nakayama
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorMasami Kanayama
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorTakeshi Oya
Department of Pathology, University of Toyama, Toyama, Japan
Search for more papers by this authorSeiichi Morita
Second Department of Surgery, University of Toyama, Toyama, Japan
Search for more papers by this authorMasakiyo Sasahara
Department of Pathology, University of Toyama, Toyama, Japan
Search for more papers by this authorDerek A. Mann
Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Search for more papers by this authorToshiro Sugiyama
Third Department of Internal Medicine, University of Toyama, Toyama, Japan
Search for more papers by this authorAbstract
Background/Aims: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are the hepatic manifestation of metabolic syndrome. However, its therapeutic strategy has not been established. Recently, an angiotensin II type 1 receptor blocker, telmisartan (Tel), has received a great deal of attention as a therapeutic tool for metabolic syndrome. The aim of this study was to investigate the efficacy and mechanisms of Tel on a murine NASH model.
Methods: C57BL/6 mice were fed a methionine- and choline-deficient high-fat diet (MCDHF) or a standard diet with/without the administration of Tel (10 mg/kg/day) for 8 weeks.
Results: MCDHF feeding induced marked steatohepatitis with macrophage infiltration. Tel attenuated liver steatosis with decreased hepatic triglycerides (P<0.05) and fibrogenesis with decreased type I collagen and transforming growth factor-β1 mRNA expressions (P<0.05). Tel also suppressed the infiltration of macrophages into the liver and decreased hepatic monocyte chemoattractant protein-1 and its receptor (CC-chemokine receptor 2; CCR2) mRNA expressions, especially CCR2. In vitro, Tel suppressed CCR2 expression, which was induced by low-density lipoprotein. The size of adipocyte in visceral fat tissue was reduced with an increased serum adiponectin concentration in the Tel group.
Conclusions: In this study, we revealed that Tel attenuated steatohepatitis progression by suppressing the macrophage infiltration into the liver. Tel also affected the reduction of adipocyte size and elevation of serum adiponectin. Tel might serve as a new therapeutic strategy for NASH.
Supporting Information
Table S1. Genes used in real-time RT-PCR analysis.
Table S2. Effect of MCDHF and Tel on organ weight.
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| LIV_2006_sm_tableS2.ppt57 KB | Supporting info item |
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References
- 1 Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989; 20: 594–8.
- 2 Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insuline resistance syndrome. Hepatology 2002; 35: 373–9.
- 3 Powell EE, Cooksley W, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990; 11: 74–80.
- 4 Yoshiji H, Kuriyama S, Yoshiji J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001; 34: 745–50.
- 5 Richey JM, Ader M, Moore D, Bergman RN. Angiotensin II induces insulin resistance independent of changes in interstitial insulin. Am J Physiol 1999; 277: 920–6.
- 6 Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507–14.
- 7 Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004; 40: 1222–5.
- 8 Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297–307.
- 9 Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004; 43: 993–1002.
- 10 Schupp M, Clemenz M, Gineste R, et al. Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 2005; 54: 3442–52.
- 11 Han KH, Tangirala RK, Green SR, Quehenberger O. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL. Arterioscler Thromb Vasc Biol 1998; 18: 1983–91.
- 12 Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288–95.
- 13 Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114: 147–52.
- 14 Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112: 91–100.
- 15 Kamada Y, Tamura S, Kiso S, et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 2003; 125: 1796–807.
- 16 Maeda N, Takahashi M, Funahashi T, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50: 2094–9.
- 17 Qiang L, Wang H, Farmer SR. Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha. Mol Cell Biol 2007; 27: 4698–707.
- 18 Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004; 429: 771–6.
- 19 Weisberg SP, Mccann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–808.
- 20 Ishibashi M, Hiasa K, Zhao Q, et al. Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling. Circ Res 2004; 94: 1203–10.
- 21 Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116: 115–24.
- 22 Haukeland JW, Damas JK, Konopski Z, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006; 44: 1167–74.
- 23 Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000; 343: 1467–76.
- 24 Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115: 56–65.
- 25 Pessayre D, Berson A, Fromntry B, Mansouri A. Mitochondria in steatohepatitis. Semin Liver Dis 2001; 21: 57–69.
- 26 Osmundsen H, Bremer J, Pedersen JI. Metabolic aspects of peroxisomal beta-oxidation. Biochim Biophys Acta 1991; 1085: 141–58.
- 27 Asehnoune K, Strassheim D, Mitra S, Kim JY, Abraham E. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J Immunol 2004; 172: 2522–9.
- 28 Fox ES, Brower JS, Bellezzo JM, Leingang KA. N-acetylcysteine and alpha-tocopherol reverse the inflammatory response in activated rat Kupffer cells. J Immunol 1997; 158: 5418–23.
- 29 Tanaka T, Fukunaga Y, Itoh H, et al. Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor gamma for monocyte recruitment and endothelial regeneration. Eur J Pharmacol 2005; 508: 255–65.
- 30 Hirose A, Ono M, Saibara T, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 2007; 5: 1375–81.
- 31 Fijita K, Yoneda M, Wada K, et al. Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Dig Dis Sci 2007; 52: 3455–64.
- 32 Jin H, Yamamoto N, Uchida K, Terai S, Sakaida I. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient l-amino acid-defined diet. Biochem Biophys Res Commun 2007; 364: 801–7.
- 33 Okuno A, Tamemoto H, Tobe K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101: 1354–61.
- 34 Yamauchi T, Kamon J, Waki H, et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001; 276: 41245–54.
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