title: Identification of a cytochrome P4502E1/Bid/C1q-dependent axis mediating inflammation in adipose tissue after chronic ethanol feeding to mice.
abstract: Chronic, heavy alcohol exposure results in inflammation in adipose tissue, insulin resistance, and liver injury. Here we have identified a CYP2E1/Bid/C1q-dependent pathway that is activated in response to chronic ethanol and is required for the development of inflammation in adipose tissue. Ethanol feeding for 25 days to wild-type (C57BL/6J) mice increased expression of multiple markers of adipose tissue inflammation relative to pair-fed controls independent of increased body weight or adipocyte size. Ethanol feeding increased the expression of CYP2E1 in adipocytes, but not stromal vascular cells, in adipose tissue and Cyp2e1(-/-) mice were protected from adipose tissue inflammation in response to ethanol. Ethanol feeding also increased the number of TUNEL-positive nuclei in adipose tissue of wild-type mice but not in Cyp2e1(-/-) or Bid (-/-) mice. Apoptosis contributed to adipose inflammation, as the expression of multiple inflammatory markers was decreased in mice lacking the Bid-dependent apoptotic pathway. The complement protein C1q binds to apoptotic cells, facilitating their clearance and activating complement. Making use of C1q-deficient mice, we found that activation of complement via C1q provided the critical link between CYP2E1/Bid-dependent apoptosis and onset of adipose tissue inflammation in response to chronic ethanol. In summary, chronic ethanol increases CYP2E1 activity in adipose, leading to Bid-mediated apoptosis and activation of complement via C1q, finally resulting in adipose tissue inflammation. Taken together, these data identify a novel mechanism for the development of adipose tissue inflammation that likely contributes to the pathophysiological effects of ethanol.
authors.affiliation: Liver Disease Research Center, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Becky M
authors.initials: BM
authors.lastname: Sebastian
authors.affiliation: Liver Disease Research Center, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.affiliation: Liver Disease Research Center, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Liver Disease Research Center, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Antoinette D
authors.initials: AD
authors.lastname: Hillian
authors.affiliation: Liver Disease Research Center, Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Liver Disease Research Center, Department of Pediatric Gastroenterology, Cleveland Clinic, Cleveland, Ohio 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland Ohio, 44190.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.affiliation: Department of Anesthesiology, Peroperative, and Pain Medicine, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
authors.affiliation: Laboratory of Developmental Immunology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Kazue
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Liver Disease Research Center, Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland Ohio, 44190; Liver Disease Research Center, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio 44195. Electronic address: nagyL3@ccf.org.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000493:pharmacokinetics; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002492:Central Nervous System Depressants; D000431:Ethanol; D015922:Complement C1q; D019392:Cytochrome P-450 CYP2E1