Ethanol-induced liver injury: preventing apoptosisAuthor InfoSocial Media
2010, Doctor of Philosophy, Case Western Reserve University, Nutrition.
Ethanol exposure induces hepatocellular apoptosis. Here we investigated the impact of apoptosis on ethanol induced liver injury using both pharmacological and genetic approaches. Thioredoxin (Trx), a potent antioxidant and anti-inflammatory molecule with anti-apoptotic properties, protects animals from a number of inflammatory diseases. However, the effects of ethanol on Trx or its role in ethanol-induced liver injury are not known. Female C57BL/6 mice were allowed free access to a Lieber-deCarli ethanol containing diet 5% (total calories) for 2 days and 32% for 2 days or pair-fed control diet. Hepatic Trx-1 was decreased by ethanol feeding; treatment with recombinant human Trx (rhTrx) prevented this decrease. Mice were treated with a daily intraperitoneal injection of either rhTrx or PBS. Ethanol feeding increased accumulation of hepatic 4-hydroxynonenal (4-HNE) protein adducts, expression of tumor necrosis factor (TNF) and resulted in hepatic steatosis and increased plasma liver enzymes. In ethanol-fed mice, treatment with rhTrx reduced these injury markers. Ethanol feeding increased apoptotic markers in the liver. rhTrx treatment prevented these increases. In summary, rhTrx attenuated ethanol-induced increases in markers of oxidative stress, inflammatory cytokine expression, and apoptosis. C1q, the recognition subunit of the first complement component, is associated with apoptotic cells. I hypothesized that ethanol-induced apoptosis acts as a signal to activate complement via C1q. Wild-type and C1q-/- mice were allowed free access to ethanol containing diets or pair-fed control diets for 4 days (11%) or 25 days (32%). Ethanol increased macrophage apoptosis in wild type and C1q-/- mice after 4 days of ethanol exposure. In contrast, immunoreactive C1q and C3b were detected in hepatic sinusoids in wild type mice, but not in C1q-/- mice, after 4 days of ethanol exposure. C1q-/- mice were protected from ethanol-induced TNF and IL-6 expression at this early time point. After 25 days of ethanol feeding, hepatocyte apoptosis and plasma ALT and AST, were attenuated in C1q-/- mice compared to wild type mice. Wild-type mice also had increased parencymal C1q and C3b deposition. Taken together, these data suggest that C1q is required for the activation of complement by ethanol and thereby contributes to the development of ethanol-induced liver injury.
Laura Nagy, PhD (Advisor)
Edith Lerner, PhD (Committee Chair)
Colleen Croniger, PhD (Committee Member)
Danny Manor, PhD (Committee Member)
John Mieyal, PhD (Committee Member)
ethanol; apoptosis; thioredoxin; complement
Cohen, J. (2010). Ethanol-induced liver injury: preventing apoptosis. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/
Cohen, Jessica. "Ethanol-induced liver injury: preventing apoptosis." Electronic Thesis or Dissertation. Case Western Reserve University, 2010. OhioLINK Electronic Theses and Dissertations Center. 24 Apr 2014.
Cohen, Jessica I. "Ethanol-induced liver injury: preventing apoptosis." Electronic Thesis or Dissertation. Case Western Reserve University, 2010. https://etd.ohiolink.edu/