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Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model.
Am J Physiol Gastrointest Liver Physiol. 2004 Jul; 287(1):G264-73.AJ

Abstract

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.

Authors+Show Affiliations

Department of Pediatrics, Children's Memorial Institute for Education and Research, Northwestern University, 2300 Children's Plaza, box 212, Chicago, IL 60614, USA. a-sahai@northwestern.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15044174

Citation

Sahai, Atul, et al. "Upregulation of Osteopontin Expression Is Involved in the Development of Nonalcoholic Steatohepatitis in a Dietary Murine Model." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 287, no. 1, 2004, pp. G264-73.
Sahai A, Malladi P, Melin-Aldana H, et al. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G264-73.
Sahai, A., Malladi, P., Melin-Aldana, H., Green, R. M., & Whitington, P. F. (2004). Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. American Journal of Physiology. Gastrointestinal and Liver Physiology, 287(1), G264-73.
Sahai A, et al. Upregulation of Osteopontin Expression Is Involved in the Development of Nonalcoholic Steatohepatitis in a Dietary Murine Model. Am J Physiol Gastrointest Liver Physiol. 2004;287(1):G264-73. PubMed PMID: 15044174.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. AU - Sahai,Atul, AU - Malladi,Padmini, AU - Melin-Aldana,Hector, AU - Green,Richard M, AU - Whitington,Peter F, Y1 - 2004/03/25/ PY - 2004/3/27/pubmed PY - 2004/7/24/medline PY - 2004/3/27/entrez SP - G264 EP - 73 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 287 IS - 1 N2 - The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/15044174/Upregulation_of_osteopontin_expression_is_involved_in_the_development_of_nonalcoholic_steatohepatitis_in_a_dietary_murine_model_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00002.2004?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -