The BAFFling problem of B cell-activating factor in nonalcoholic fatty liver disease.

Abstract

Nonalcoholic fatty liver disease (NAFLD) has emerged as aglobal health problem together with the obesity and diabetesepidemic. Currently, the spectrum of NAFLD is definedhistologically as nonalcoholic fatty liver alone or simplesteatosis (NAFL or SS) and nonalcoholic steatohepatitis(NASH) with or without fibrosis. Histologic details aboutsteatosis and inflammation, cytologic ballooning, and Mal-lory-Denk bodies help characterize the disease spectrum.However, a noninvasive alternative to histology is presentlyunavailable and is an area of active investigation.Obesity, insulin resistance, inflammation, and oxidativestress play significant roles in the development and pro-gression of NAFLD (Fig. 1). The long-term outcome ofNAFLD is influenced by the histologic spectrum (devel-opment of cirrhosis in up to 3–5 % of SS vs. 15–20 % ofNASH patients). Thus, the distinction between SS andNASH is important; however, it requires a liver biopsy.Noninvasive means to differentiate the spectrum of NA-FLD is being actively explored. In the current issue ofHepatology International, Miyake et al. have presenteddata on B cell-activating factor (BAFF) in an attempt toidentify blood-based markers to distinguish SS fromNASH.The B cell-activating factor (BAFF, also known asBLyS, TALL-1, CD257) is a tumor necrosis factor (TNF)superfamily (TNFSF13B) member that promotes theexpansion and differentiation of the B cell populationleading to increased serum immunoglobulin levels [1, 2].BAFF is an important regulator of peripheral B cellmaturation, survival, immunoglobulin production andimmunoglobulin class-switch recombination (CSR), abiological mechanism by which activated B cells (plasmacells) change their antibody production from one isotype toanother, for example, from IgM to IgG [3].BAFF is mainly produced and secreted by myeloid cells(macrophages, monocytes, and dendritic cells) and also bynonlymphoid cell types and epithelial cells [3–5]. It isexpressed as a type II transmembrane protein (biologicallyactive 17-kDa molecule), and levels of BAFF are upregu-lated by interferon (IFN)-c, interleukin (IL)-10, and CD40ligand produced during inflammation and/or chronicinfections [6].The biological role of BAFF is mediated by three spe-cific receptors (Fig. 2). BAFF receptor (BAFF-R) andtransmembrane activator-calcium modulator and cyclo-philin ligand interactor (TACI) are high-affinity receptors,while B cell maturation antigen (BCMA) is a low-affinityreceptor [7–9]. BAFF is synthesized as a membrane-boundprotein and is released as soluble BAFF by proteolysis.Soluble BAFF can then either remain as a homotrimer ortransform into a capsid-like assembly of 20 trimers (60-mer) following oligomerization (Fig. 2). Downstream sig-naling is mediated through TNF receptor-associated factors(TRAFs). The recruitment of TRAF3 to trimeric BAFF-Ractivates the alternative nuclear factor-jB2 (NF-jB2) sig-naling pathway. In contrast, the recruitment of TRAF2 orTRAF6 to trimeric TACI initiates the classical NF-jB1pathway.Recent evidence points to an emerging role of BAFF inadipocyte biology [10–13]. Alexaki and colleagues [10]identified BAFF-R in human adipocytes from visceraladipose tissue (VAT). Further, Hamada et al. [11] dem-onstrated that BAFF-treated mice had higher TNF-a, IL-6,and resistin gene expression in VAT, while adiponectin