title: The Role of miR-212 and iNOS in Alcohol-Induced Intestinal Barrier Dysfunction and Steatohepatitis.
abstract: BACKGROUND
  Alcoholic liver disease is commonly associated with intestinal barrier dysfunction. Alcohol-induced dysregulation of intestinal tight junction proteins, such as Zonula Occludens-1 (ZO-1), plays an important role in alcohol-induced gut leakiness. However, the mechanism of alcohol-induced disruption of tight junction proteins is not well established. The goal of this study was to elucidate this mechanism by studying the role of microRNA 212 (miR-212) and inducible nitric oxide synthase (iNOS) in alcohol-induced gut leakiness.
  
  
  METHODS
  The permeability of the Caco-2 monolayer was assessed by transepithelial electrical resistance and flux of fluorescein sulfonic acid. miR-212 was measured by real-time polymerase chain reaction. The wild-type, iNOS knockout, and miR-212 knockdown mice were fed with alcohol diet (29% of total calories, 4.5% v/v) for 8 weeks. The LNA-anti-miR-212 was used to inhibit miR-212 expression in mice. The alcohol-induced intestinal permeability, miR-212 expression, and liver injuries in mice were measured.
  
  
  RESULTS
  Our in vitro monolayer and in vivo mice studies showed that: (i) alcohol-induced overexpression of the intestinal miR-212 and intestinal hyperpermeability is prevented using miR-212 knockdown techniques; and (ii) iNOS is up-regulated in the intestine by alcohol and that iNOS signaling is required for alcohol-induced miR-212 overexpression, ZO-1 disruption, gut leakiness, and steatohepatitis.
  
  
  CONCLUSIONS
  These studies thus support a novel miR-212 mechanism for alcohol-induced gut leakiness and a potential target that could be exploited for therapeutic intervention to prevent leaky gut and liver injury in alcoholics.
authors.affiliation: Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Forsyth
authors.affiliation: Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Maliha
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Song
authors.affiliation: Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018938:Caco-2 Cells; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D010539:Permeability / Q000187:drug effects
chemical_list: D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Alcoholic Liver Disease; Inducible Nitric Oxide Synthase; Intestinal Permeability; MicroRNA 212; Zonula Occludens-1