LAUSR

Non-alcoholic fatty liver disease (NAFLD), and its subtype nonof NASH while forcing its expression restrains hepatic inflammation, alcoholic steatohepatitis (NASH), prevalence is increasing worldwide leading to major complications such as cirrhosis and hepatocellular carcinoma (HCC) [1]. An exact assessment of NAFLD prevalence is still difficult given the lack of sensitive and specific biomarkers to avoid histological assessment which needs liver biopsy. Similarly, the lack of appropriate therapeutic agents to modify the biology of the disease is a main limit to prevent its complications. In this issue of EBioMedicine Yanan Cao and coworkers describe an intriguing cross-talk between microRNA 221/222 and TIMP3 [2], an inhibitor of metalloproteinase previously involved in hepatic inflammation and steatosis [3,4]. Using genetically modified mouse models the authors were able to knockdown miR-221/222 specifically in the hepatocyte which led to a dramatic reduction of inflammation, steatosis and fibrosis when the mice were exposed to agents inducing NASH such as methionine and choline deficient diet or CCl4 treatment. The highly conserved cluster miR-221 and 222 has been reported in HCC, liver of NASH patients [5,6] and they are believed to affect tumorigenesis process [6]. To provide evidence that miR-221/22 are functionally related to NASH progression Yanan Cao and coworkers performed both targeted inhibition of miR-221/222 by locked nucleic acid (LNA)anti-miRNA and re-expressionofmiR-221/222 in vivo [2]. These elegant experiments provided a clear role for the miR-221/222 cluster in NASH pathogenesis. Furthermore, the miR-221/222 inhibitors could be candidate in miRNA-based gene therapies for the intervention of NASH. Given the broad effects of miR-221/222 they also looked for target genes and among many candidates that were involved in metabolic and inflammatory pathways such as PGC-1b (Ppargc1b), glucose-6phosphatase-α (G6pc), Ddit4 and Bmf, they focused on Timp3 (tissue inhibitor of metalloproteinase 3). Timp3 is a secreted protein that once bound to extracellularmatrix retains the ability to block activation of several cell-membrane metalloproteases such as ADAM-17, the TNFalpha converting enzyme, and other members of the ADAM family which control EGFR and NOTCH signaling pathways. Experimental models revealed that lack of TIMP3 accelerate the onset and progression