Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals

Ikejima, Kenichi; Honda, Hiroki; Yoshikawa, Mutsuko; Hirose, Miyoko; Kitamura, Tsuneo; Takei, Yoshiyuki; Sato, Nobuhiro

doi:10.1053/jhep.2001.26518

Cited by 266 publications

(185 citation statements)

References 44 publications

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“…Rodent models have suggested that leptin may augment hepatic inflammation and fibrosis 29,30 ; however, it must be remembered that our patients with hypoleptinemia had NASH with fibrosis at baseline. Thus, the relationship between rodent models and the human condition is unclear.…”

Section: Discussionmentioning

confidence: 87%

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

et al. 2005

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Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P ‫؍‬ .006) and ballooning injury (P ‫؍‬ .005), with a reduction of mean NASH activity by 60% (P ‫؍‬ .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (12063226 mg/dL, P ‫؍‬ .002), glucose (2203144 mg/dL, P ‫؍‬ .02), insulin (46.4324.8 IU/mL, P ‫؍‬ .004), ALT (54324 U/L, P ‫؍‬ .02), AST (47322 U/L, P ‫؍‬ .046), liver volume (320932391 cm 3 , P ‫؍‬ .007), and liver fat content (31311%, P ‫؍‬ .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH. (HEPATOLOGY 2005;41:753-760.) N onalcoholic steatohepatitis (NASH), a progressive metabolic liver disease, is one of the major consequences of the current obesity epidemic. 1-3 It lies on a spectrum of nonalcoholic fatty liver disease that ranges from ectopic lipid accumulation (steatosis) to cirrhosis. 4 Steatosis is believed to sensitize the liver to metabolic injury, leading to inflammation, necrosis, and fibrosis. 2,5-7 Thus, steatosis is a constant feature of NASH, but NASH is only distinguishable by liver biopsy. The assessment and severity of NASH is made histologically based on the patterns and degrees of hepatic steatosis, inflammation, and injury, in the absence of significant alcohol consumption. 8 Although steatosis is seen in both animal and human models, NASH is only fully appreciated in the human condition. 7 Thus, human models of NASH are critical for the development of therapeutic strategies for this condition.Steatosis occurs with decreased leptin action, whether due to leptin deficiency or resistance. 9 Lipodystrophy repr...

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Section: Discussionmentioning

confidence: 87%

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

et al. 2005

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“…7 The in situ murine hepatoma model was established as previously described. 8 In brief, mouse hepatoma ML1 cells were injected into the mouse spleen, and after colonizing in the spleen, ML1 migrated to the liver, forming different sizes of hepatoma nodules.…”

Section: Materials and Methods Mouse Modelmentioning

confidence: 99%

Induction of liver fibrosis in a murine hepatoma model by thioacetamide is associated with enhanced tumor growth and suppressed antitumor immunity

Yang

Chang

Lei

2010

Laboratory Investigation

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Liver cirrhosis and hepatocellular carcinomas are two major causes of morbidity and mortality worldwide, and can synergistically interact to expedite the tumor progression. How fibrosis promotes the hepatoma growth remains completely unexplained. Using an in situ murine hepatoma model together with fibrosis induction by thioacetamide (TAA), the hepatoma growth and the immune factors in the fibrotic liver were analyzed. We found that TAA-fibrosis induction enhanced hepatoma cell growth in the liver and increased the mortality of hepatoma-bearing mice. The tumor-infiltrating CD4 þ or CD8 þ T cells are downregulated by fibrosis induction. The Foxp3 þ regulatory T cells (Treg) cells were induced. We conclude that fibrosis induction causes further immunosuppression, in which Treg cells exert a downregulation effect on the antitumor immunity.

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“…Mice (n Ն 3 in each group) were administered CCl 4 (0.1 L/g body wt in olive oil) and/or recombinant murine leptin (1 g/g body weight) simultaneously via intraperitoneal injection and sacrificed after 24 hours. 11 Six-week-old ob/ob mice and their lean littermates were obtained from The Jackson Laboratory (Bar Harbor, ME). Animals (n Ն 3 in each group) were treated with a single intraperitoneal injection of CCl 4 (1 L/kg body weight) and sacrificed after 48 hours.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells

et al. 2005

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Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals

Cited by 266 publications

References 44 publications

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

Induction of liver fibrosis in a murine hepatoma model by thioacetamide is associated with enhanced tumor growth and suppressed antitumor immunity

Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells

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