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Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease.

Publication ,  Journal Article
Syn, W-K; Oo, YH; Pereira, TA; Karaca, GF; Jung, Y; Omenetti, A; Witek, RP; Choi, SS; Guy, CD; Fearing, CM; Teaberry, V; Pereira, FEL ...
Published in: Hepatology
June 2010

UNLABELLED: Liver inflammation is greater in nonalcoholic steatohepatitis (NASH) than steatosis, suggesting that immune responses contribute to nonalcoholic fatty liver disease (NAFLD) progression. Livers normally contain many natural killer T (NKT) cells that produce factors that modulate inflammatory and fibrogenic responses. Such cells are relatively depleted in steatosis, but their status in more advanced NAFLD is uncertain. We hypothesized that NKT cells accumulate and promote fibrosis progression in NASH. We aimed to determine if livers become enriched with NKT cells during NASH-related fibrosis; identify responsible mechanisms; and assess if NKT cells stimulate fibrogenesis. NKT cells were analyzed in wildtype mice and Patched-deficient (Ptc(+/-)) mice with an overly active Hedgehog (Hh) pathway, before and after feeding methionine choline-deficient (MCD) diets to induce NASH-related fibrosis. Effects of NKT cell-derived factors on hepatic stellate cells (HSC) were examined and fibrogenesis was evaluated in CD1d-deficient mice that lack NKT cells. NKT cells were quantified in human cirrhotic and nondiseased livers. During NASH-related fibrogenesis in wildtype mice, Hh pathway activation occurred, leading to induction of factors that promoted NKT cell recruitment, retention, and viability, plus liver enrichment with NKT cells. Ptc(+/-) mice accumulated more NKT cells and developed worse liver fibrosis; CD1d-deficient mice that lack NKT cells were protected from fibrosis. NKT cell-conditioned medium stimulated HSC to become myofibroblastic. Liver explants were 2-fold enriched with NKT cells in patients with non-NASH cirrhosis, and 4-fold enriched in patients with NASH cirrhosis. CONCLUSION: Hh pathway activation leads to hepatic enrichment with NKT cells that contribute to fibrosis progression in NASH.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

June 2010

Volume

51

Issue

6

Start / End Page

1998 / 2007

Location

United States

Related Subject Headings

  • Signal Transduction
  • Natural Killer T-Cells
  • Mice, Inbred C57BL
  • Mice
  • Methionine
  • Liver
  • Humans
  • Hepatic Stellate Cells
  • Hedgehog Proteins
  • Gastroenterology & Hepatology
 

Citation

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Syn, W.-K., Oo, Y. H., Pereira, T. A., Karaca, G. F., Jung, Y., Omenetti, A., … Diehl, A. M. (2010). Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology, 51(6), 1998–2007. https://doi.org/10.1002/hep.23599
Syn, Wing-Kin, Ye Htun Oo, Thiago A. Pereira, Gamze F. Karaca, Youngmi Jung, Alessia Omenetti, Rafal P. Witek, et al. “Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease.Hepatology 51, no. 6 (June 2010): 1998–2007. https://doi.org/10.1002/hep.23599.
Syn W-K, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology. 2010 Jun;51(6):1998–2007.
Syn, Wing-Kin, et al. “Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease.Hepatology, vol. 51, no. 6, June 2010, pp. 1998–2007. Pubmed, doi:10.1002/hep.23599.
Syn W-K, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, Teaberry V, Pereira FEL, Adams DH, Diehl AM. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology. 2010 Jun;51(6):1998–2007.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

June 2010

Volume

51

Issue

6

Start / End Page

1998 / 2007

Location

United States

Related Subject Headings

  • Signal Transduction
  • Natural Killer T-Cells
  • Mice, Inbred C57BL
  • Mice
  • Methionine
  • Liver
  • Humans
  • Hepatic Stellate Cells
  • Hedgehog Proteins
  • Gastroenterology & Hepatology