1. Volume 132, Issue 1, Pages 282-293 (January 2007)
Insulin Resistance Accelerates a Dietary Rat Model of Nonalcoholic Steatohepatitis 
Tsuguhito Ota, Toshinari Takamura, Seiichiro Kurita, Naoto Matsuzawa, Yuki Kita, Masafumi Uno, Hiroshi Akahori, Hirofumi Misu, Masaru Sakurai, Yoh Zen, Yasuni Nakanuma, Shuichi Kaneko 
Gastroenterology 
Volume 132, Issue 1, Pages (January 2007)
DOI: /j.gastro
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2. Figure 1
Effect of obese diabetes background or high-fat (HF) diet on insulin sensitivity and its improvement by pioglitazone (PGZ) in methionine- and choline-deficient (MCD) diet-induced rats with nonalcoholic steatohepatitis. Blood glucose levels during the oral glucose tolerance test (A) and intraperitoneal insulin tolerance test (ITT) (B) in the MCD and MCD+HF diet fed to Otsuka Long-Evans Tokushima Fatty (OLETF) compared with the MCD diet fed to Long-Evans Tokushima Otsuka (LETO) rats at 8 weeks. Effect of PGZ on blood glucose levels during ITT of MCD-diet OLETF rats at 8 weeks (C). Values are mean ± SEM (n = 5–8). Values are expressed relative to basal blood glucose levels designated as 100% in B and C. The area under curve (AUC) of the percent of basal glucose during the ITT is described in Materials and Methods. *P < .05 vs LETO rats fed the MCD diet. †P < .05 vs OLETF rats fed the MCD diet.
Gastroenterology  , DOI: ( /j.gastro )
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3. Figure 2
Insulin resistance and obese diabetes accelerate the pathology in an animal model of nonalcoholic fatty liver disease. Representative photomicrographs showing the effect of a methionine- and choline-deficient (MCD), MCD+high-fat (MCD+HF), and MCD with pioglitazone treatment (MCD+PGZ) diet on liver histology in Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats at 8 weeks. Rats were fed each diet for 8 weeks, and paraffin-embedded sections were stained with H&E (A) or Azan (B) stain. Hepatocyte ballooning is shown in insets. Arrows indicate infiltration of the inflammatory cells in hepatic parenchyma. Original magnification, 100X. Time course of histologic changes in liver was in LETO rats fed MCD diet (MCD-LETO) and OLETF rats fed MCD (MCD-OLETF) or MCD+HF diet (MCD+HF-OLETF) for 2, 4, and 8 weeks shown as histologic scores (C). Criteria for each score are described in Materials and Methods. Black circles = MCD-LETO; black squares = MCD-OLETF; black triangles = MCD+HF-OLETF. Histologic diagnosis at 8 weeks (D). Values are mean ± SEM (n = 5-8).
Gastroenterology  , DOI: ( /j.gastro )
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4. Figure 3
Steatosis precedes inflammation, which leads to fibrosis in the development of nonalcoholic steatohepatitis. Time course of histologic changes in liver stained with H&E (A) or Azan (B) stain in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a methionine- and choline-deficient (MCD) or MCD+ high-fat (HF) diet for 2 weeks (left column), 4 weeks (middle column), and 8 weeks (right column). Original magnification, 100X.
Gastroenterology  , DOI: ( /j.gastro )
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5. Figure 4
Insulin resistance and obese diabetes accelerate liver injury along with fat accumulation in the liver; both are improved by pioglitazone treatment. Hepatic triglycerides content (A) and plasma ALT levels (B) for each diet in Long-Evans Tokushima Otsuka (LETO) or Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 8 weeks. Control (white bars, n = 8), methionine- and choline-deficient (MCD) (black bars, n = 8), MCD+high-fat (MCD+HF, dark gray bars, n = 6) and MCD with pioglitazone treatment (MCD+PGZ, light gray bars, n = 5) diet-fed OLETF or LETO rats. Values are mean ± SEM. *P < .05, **P < .01 vs control diet.
Gastroenterology  , DOI: ( /j.gastro )
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6. Figure 5
Activation of stellate cells in dietary model of nonalcoholic steatohepatitis, which is improved by pioglitazone treatment. Immunohistochemical staining with anti-α-SMA antibody and hematoxylin in the liver from a Long-Evans Tokushima Otsuka (LETO) (A) or Otsuka Long-Evans Tokushima Fatty (OLETF) (B) rats treated with methionine- and choline-deficient (MCD), MCD+high-fat (MCD+HF), MCD with pioglitazone treatment (MCD+PGZ), or control diet at 8 weeks. Positive staining was observed in perivenular (arrows) and pericelluar (arrowheads) region. Sections are counterstained with hematoxylin. Original magnification, 100X.
Gastroenterology  , DOI: ( /j.gastro )
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7. Figure 6
Insulin resistance and obese diabetes up-regulate hepatic mRNA expression of fibrogenic genes and its improvement by pioglitazone treatment in methionine- and choline-deficient (MCD) diet-induced rat model of nonalcoholic steatohepatitis. Effects of MCD, MCD+high-fat (MCD+HF), and MCD with pioglitazone treatment (MCD+PGZ) diet on (A) transforming growth factor-β (TGF-β), (B) α1 (I) procollagen (collagen I), and (C) plasminogen activator-1 (PAI-1) mRNA expression in the liver. The time course of hepatic mRNA expression for TNF-α, PAI-1, TGF-β, and collagen I in MCD+HF diet fed to Long-Evans Tokushima Otsuka (LETO) or Otsuka Long-Evans Tokushima Fatty (OLETF) rats (D). Hepatic expression of TNF-α gene precedes that of fibrogenic genes. Gene expressions were assessed using real-time RT-PCR and normalized with 18S ribosomal RNA (rRNA) mRNA. Control (white bars, n = 8), MCD (black bars, n = 8), MCD+HF (dark gray bars, n = 6) and MCD+PGZ (light gray bars, n = 5), diet-fed OLETF or LETO rats at 8 weeks. Values are mean ± SEM. *P < .05, **P < .01 vs control diet (A–C), *P < .05 vs values at baseline (0 week) in each gene (D).
Gastroenterology  , DOI: ( /j.gastro )
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8. Figure 7
Effects of high-fat diet and pioglitazone treatment on hepatic mRNA expression of lipogenic genes in methionine- and choline-deficient (MCD) diet-induced rat of nonalcoholic steatohepatitis. Effects of high-fat (MCD+HF) and pioglitazone treatment (MCD+PGZ) diet on (A) sterol regulatory element-binding protein (SREBP)-1c, (B) fatty acid synthase (FAS), (C) and stearoyl-CoA desaturase (SCD)-1 mRNA expression in the liver of MCD diet-induced rat of nonalcoholic steatohepatitis. Gene expressions were assessed using real-time RT-PCR and normalized with 18S ribosomal RNA (rRNA) mRNA. MCD (black bars, n = 8), MCD+HF (dark gray bars, n = 6), and MCD+PGZ (light gray bars, n = 5), diet-fed OLETF or LETO rats at 8 weeks. Values are mean ± SEM. *P < .01, **P < .001 vs MCD diet.
Gastroenterology  , DOI: ( /j.gastro )
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