Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat

Gastroenterology. 2002 May;122(5):1399-410. doi: 10.1053/gast.2002.32995.

Abstract

Background & aims: In this study, we investigated the role of leptin and its receptors (Ob-R) in profibrogenic responses in the liver using Zucker (fa/fa) rats, a natural occurring Ob-R-deficient animal.

Methods: Male Zucker (fa/fa) rats and their lean (+/?) littermates were given intraperitoneal injections of thioacetamide (TAA) (200 mg/kg body wt, 3 times/wk) for 4-8 weeks, and progression of hepatic fibrosis was evaluated. In vitro transactivation of hepatic stellate cells (HSCs) isolated from Zucker rats was evaluated by Western blotting and immunocytochemistry for alpha-smooth muscle actin and type I collagen. Further, a long-form Ob-R (Ob-Rb) in sinusoidal endothelial cells (SECs) and Kupffer cells was identified by reverse-transcription polymerase chain reaction. Moreover, transforming growth factor (TGF)-beta1 messenger RNA in LSE cells, a human SEC-derived cell line, was measured by Northern blotting.

Results: Although the normal liver does not produce leptin, activated HSCs produced leptin in vivo during fibrogenesis caused by TAA. In Zucker rats, TAA-induced hepatic fibrosis was prevented almost completely, whereas induction of TGF-beta1 and activation of HSCs were abolished. It is less likely, however, that leptin plays an essential role in the activation of HSCs as a strong autocrine regulator, because HSCs isolated from Zucker rats undergo normal transactivation process in vitro. In contrast, SECs and Kupffer cells contain Ob-Rb, through which leptin up-regulates the expression of matrix remodeling genes including TGF-beta1.

Conclusions: Collectively, these findings indicated that leptin and its functional receptors (Ob-Rb) play a pivotal role in profibrogenic responses in the liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Extracellular Matrix / metabolism*
  • Humans
  • Leptin / biosynthesis
  • Liver Cirrhosis, Experimental / etiology*
  • Male
  • Rats
  • Rats, Wistar
  • Rats, Zucker
  • Receptors, Cell Surface*
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Trans-Activators / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Leptin
  • Receptors, Cell Surface
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, rat
  • TGFB1 protein, human
  • Tgfb1 protein, rat
  • Trans-Activators
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • leptin receptor, human