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Esben Skipper Sørensen

Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice

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  • Xiadong Ge, Mount Sinai School of Medicine, United States
  • Tung-Ming Leung, Mount Sinai School of Medicine, United States
  • Elena Arriazu, Mount Sinai School of Medicine, United States
  • Yongke Lu, Mount Sinai School of Medicine, United States
  • Raquel Urtasun, Mount Sinai School of Medicine, United States
  • Brian Søndergaard Christensen
  • Maria Isabel Fiel, Mount Sinai School of Medicine, United States
  • Satoshi Mochida, Saitama Medical School, Japan
  • Esben Skipper Sørensen
  • Natalia Nieto, Mount Sinai School of Medicine, United States
Although osteopontin (OPN) is induced in alcoholic patients, its role in the pathophysiology of alcoholic liver disease (ALD) remains unclear. Increased translocation of lipopolysaccharide (LPS) from the gut is key for the onset of ALD because it promotes macrophage infiltration and activation, tumor necrosis factor-α (TNFα) production, and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout (Opn−/−), and transgenic mice overexpressing OPN in hepatocytes (OpnHEPTg) were fed either the control or the ethanol Lieber-DeCarli diet. Ethanol increased hepatic, plasma, biliary, and fecal OPN more in OpnHEPTg than in WT mice. Steatosis was less in ethanol-treated OpnHEPTg mice as shown by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining, and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower alanine aminotransferase (ALT) activity, hepatocyte ballooning degeneration, LPS levels, the inflammation score, and the number of macrophages and TNFα+ cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed binding affinity for LPS which prevented macrophage activation, reactive oxygen, and nitrogen species generation and TNFα production. Treatment with milk OPN (m-OPN) blocked LPS translocation in vivo and protected from early alcohol-induced liver injury. Conclusion: Natural induction plus forced overexpression of OPN in the liver or treatment with m-OPN protect from early alcohol-induced liver injury by blocking the gut-derived LPS and TNFα effects in the liver. (Hepatology 2014;59:1600-1616)
Original languageEnglish
Pages (from-to)1600-1616
Number of pages17
Publication statusPublished - Apr 2014

Bibliographical note

Potential conflict of interest: Dr. Mochida is on the speakers' bureau and received grants from Mitsubishi Tanabe, Chugai, MSD, Tray Industries, Bayer, Otsuka, Dainippon Sumitomo, Bristol-Myers Squibb, Astellas, and Ajinomoto.

Supported by a short-term Bancaja Fellowship and Postdoctoral Fellowship from the Asociación Española para el Estudio del Hígado, Spain (to E.A.). Postdoctoral Fellowship from the Government of Navarre, Spain (to R.U.). US Public Health Service Grants 5 R01 DK069286, 2 R56 DK069286, and 3 R56 DK069286-06S1 from the National Institute of Diabetes and Digestive and Kidney Diseases (to N.N.). US Public Health Service Grants 5 P20 AA017067, 5 P20 AA017067-01S1, 5 P20 AA017067-03S1 (to N.N. and M.I.F), and 1 U01 AA021887-01 from the National Institute on Alcohol Abuse and Alcoholism (to N.N.). The Danish Council for Independent Research (E.S.S.).

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