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The Role of miR‐212 and iNOS in Alcohol‐Induced Intestinal Barrier Dysfunction and Steatohepatitis
Author(s) -
Tang Yueming,
Zhang Lijuan,
Forsyth Christopher B.,
Shaikh Maliha,
Song Shiwen,
Keshavarzian Ali
Publication year - 2015
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12813
Subject(s) - tight junction , steatohepatitis , gene knockdown , intestinal permeability , alcoholic liver disease , chemistry , liver injury , alcohol , paracellular transport , medicine , endocrinology , microbiology and biotechnology , biology , fatty liver , permeability (electromagnetism) , biochemistry , cirrhosis , apoptosis , disease , membrane
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 micro RNA 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.