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Upregulation Of Mir21 And Repression Of Grhl3 By Leptin Mediates Sinusoidal Endothelial Injury In Experimental Nonalcoholic Steatohepatitis, Sahar Pourhoseini, Ratanesh K. Seth, Suvarthi Das, Diptadip Dattaroy, Maria B. Kadiiska, Guanhua Xie, Gregory A. Michelotti, Mitzi Nagarkatti, Anna Mae Diehl, Saurabh Chatterjee

Faculty Publications

Sinusoidal endothelial dysfunction (SED) has been found to be an early event in nonalcoholic steatohepatitis (NASH) progression but the molecular mechanisms underlying its causation remains elusive. We hypothesized that adipokine leptin worsens sinusoidal injury by decreasing functionally active nitric oxide synthase 3 (NOS)3 via miR21. Using rodent models of NASH, and transgenic mice lacking leptin and leptin receptor, results showed that hyperleptinemia caused a 4-5 fold upregulation of hepatic miR21 as assessed by qRTPCR. The upregulation of miR21 led to a time-dependent repression of its target protein Grhl3 levels as shown by western blot analyses. NOS3-p/NOS3 ratio which is controlled …