Raison has served as a speaker for Lilly and Wyeth http://www.selleckchem.com/products/arq-197.html and as a consultant or an advisory board member for Lilly and Wyeth and owns equity in ContemplativeHealth; David B. Rye has served as a consultant for Schering-Plough; Andrew H. Miller has served as a consultant for Schering-Plough, AstraZeneca, Janssen, and Centocor, and has received research funding from Centocor, GlaxoSmithKline, and Schering-Plough; Bobbi J Woolwine, Gerald Vogt, Breanne M. Bautista, and James R. Spivey reported no biomedical financial interests or potential conflicts of interest. Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

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Liver fibrosis and its end-stage manifestation of cirrhosis represent clinical challenges worldwide. Hepatic stellate cell (HSC) activation is the cardinal feature that results in hepatic fibrosis. When stimulated by reactive oxygen species or cytokines in response to various hepatic insults, quiescent HSCs are transformed to myofibroblasts (MF-HSCs) that proliferate and secrete collagen.1�C4 Studies have shown that apoptosis of activated HSCs can reverse fibrosis.

5�C13 Thus, the mechanisms that control MF-HSC apoptosis may represent potential therapeutic targets that result in reduced fibrosis.14�C16 Nogo-B, also known as reticulon 4B, is a member of the reticulon protein family that is localized primarily to the endoplasmic reticulum (ER).17,18 Four groups of reticulons (1, 2, 3, and 4) exist, and each has multiple isoforms. Reticulon 4 has three isoforms, Nogo-A, B, and C. The most recognized isoform, Nogo-A (200 kDa), a potent neural outgrowth inhibitor,19�C21 is expressed mainly in the nervous system.22�C24 Nogo-C (25 kDa) is highly expressed in the differentiated muscle fibers and somewhat in the brain,17,18,22 however, its function remains unclear. Nogo-B (55 kDa), a splice variant of Nogo-A, is expressed in most tissues and has been reported for its role in modulating endothelial and smooth muscle cellular responses after injury in a variety of organs/tissues, including blood vessels,25,26 lung,27,28 kidney,29 and liver.

30 We previously showed that the absence of Nogo-B in a murine model blocks the progression of fibrosis/cirrhosis and the development of portal hypertension.30 Further, Anacetrapib we showed that lack of Nogo-B decreases the levels of ��-smooth muscle actin (��-SMA), a marker of MF-HSCs, in murine cholestatic livers. These findings led us to hypothesize that absence of Nogo-B may increase the susceptibility of MF-HSCs to apoptosis, thereby reducing fibrosis/cirrhosis in mice.