Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model

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.

Osteopontin delays resolution of liver fibrosis

“…In conclusion, although the pro-fibrogenic effects of OPN have been demonstrated in several tissues including the liver, 17,[26][27][28][29] the role of OPN in the resolution of liver fibrosis was not explored until now. This study suggests that deletion of the Opn gene induces faster removal of fibrillar collagen-I after chronic liver injury likely due to a direct action on TIMP-1 expression and to less activated HSCs.…”

The Temporal Expression of Osteopontin (SPP-1) in the Rodent Model of Alcoholic Steatohepatitis: A Potential Biomarker

“…OPN is also known to play an important role in a variety of inflammatory diseases like glomerular nephritis Giachelli and Steitz, 2000;O'Regan and Berman, 2000), inflammation during CCl 4 induced hepatotoxicity (Kawashima et al, 1999), puromycin-induced toxicity ) and in non-alcoholic steatohepatitis (Sahai et al, 2004). The role of OPN in inflammation has been confirmed in in vivo studies, where rats treated with neutralizing OPN antibody following induction of experimental crescentic glomerulonephritis had substantially decreased accumulation of renal interstitial macrophages as compared to the controls (Yu et al, 1998).…”

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

“…Conflicting results exist, however, with regard to the role of this chemokine in the development of liver fibrosis. Whereas liver fibrosis was reduced in osteopontin knockout mice fed a methionine/ choline-deficient diet to model nonalcoholic steatohepatitis, liver fibrosis was not reduced in mice subjected to bile duct ligation [48,49]. In addition, treatment of these mice chronically with carbon tetrachloride resulted in enhanced liver fibrosis, which may have resulted from increased liver injury in these mice [50].…”