Liver X Receptor Protects against Liver Injury in Sepsis Caused by Rodent Cecal Ligation and Puncture Yun Yong Wang, 1,a Una Ryg, 1 Maria K. Dahle, 1,2 Knut R. Steffensen, 3 Christoph Thiemermann, 4 Irshad H. Chaudry, 5 Finn P. Reinholt, 6 Jon L. Collins, 7 Hilde I. Nebb, 8 Ansgar O. Aasen, 1 Jan-A ˚ ke Gustafsson, 3 and Jacob E. Wang 1,b Abstract Background: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP). Methods: Rats were subjected to CLP sepsis or a sham operation. Some were treated with the synthetic LXR agonist GW3965 0.3 mg/kg 30 min prior to the CLP procedure, and organs and plasma were harvested at 3, 10, 18, or 24 h. Organs were analyzed for RNA expression by quantitative polymerase chain reaction or for mor- phologic differences by histologic review. Organ injury and inflammatory markers were measured in plasma. Results: Expression of the LXRa gene was decreased in the livers of CLP rats compared with sham-operated rats. Administration of a synthetic agonist of LXR (GW3965) reduced biochemical indices of liver injury in the blood of CLP rats. We also demonstrated that liver injury associated with CLP is aggravated in LXRa- and LXRab- deficient mice compared with wild-type and LXRb-deficient mice, indicating a role for LXRa in protecting the liver. The enhanced liver injury in LXR-deficient mice was associated with elevated plasma concentrations of high mobility group box 1, a late mediator of inflammation and a known factor in the pathology of this model. Conclusions: Collectively, these results argue in favor of a role for LXRa in protection against liver injury in experimental sepsis induced by CLP. S epsis, a systemic inflammatory response caused by infection, continues to be the major cause of death in surgical intensive care units. Pro-inflammatory mediators ac- tivate cellular and humoral defense systems that are early manifestations of the disease. When produced excessively, these mediators may lead to injury and dysfunction of vital organs, such as the lung, heart, kidney, and liver [1]. Liver dysfunction generally occurs late in the septic process and portends a worse outcome [2,3]. Transferring these pathogenic insights into clinical therapy has proved difficult, in part be- cause of a narrow therapeutic window for effective use of specific cytokine inhibitors. In this respect, high mobility group box 1 (HMGB1) has been identified as a late mediator of sys- temic inflammation [4]. Originally described as an intracellular transcription factor, accumulating data show that HMGB1 is released from macrophages after exposure to endotoxin and tumor necrosis factor (TNF)-a and that it is an essential medi- ator of pathology and death in experimental sepsis [4] . Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily and are master regulators of cholesterol 1 Institute for Surgical Research, Oslo University Hospital Rikshospitalet HF, Oslo, Norway. 2 Department of Anatomy, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway. 3 Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden, and Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas. 4 The William Harvey Research Institute, London, United Kingdom. 5 Center for Surgical Research, University of Alabama, Birmingham, Alabama. 6 Institute of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 7 GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina. 8 Department of Nutrition, University of Oslo, Oslo, Norway. a Present address: Oslo University Hospital Radiumhospitalet, National Competence Center for Gynecological Oncology, Oslo, Norway. b Present address: Department of Biology and Biomedicine, The Research Council of Norway, Oslo, Norway. SURGICAL INFECTIONS Volume 12, Number 4, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/sur.2010.066 1