The current studies used a high trans-fat, high fructose diet to promote murine NAFLD with fibrosis,18 revealing that L-Fabp−/− mice not only exhibit attenuated steatosis with decreased LD accumulation but are also protected against steatosis-associated fibrogenesis. Several elements of these findings merit additional discussion. Little is known about the expression of genes related to FA uptake and metabolic channeling during HSC activation. Earlier studies in freshly isolated rat HSCs revealed expression

of mRNAs encoding Brain-Fabp (B-Fabp, Fabp7), L-Fabp, as well as retinol binding protein Epigenetics inhibitor (Rbp), with decreased expression upon culture in vitro.23 The current findings in murine HSCs confirm some but not all of those findings (specifically, B-Fabp was undetectable in our hands) but also demonstrate that L-Fabp depletion temporally accompanies LD depletion from cultured WT murine HSCs and that HSCs isolated from L-Fabp−/− mice AG-014699 in vitro contain

fewer LDs. Importantly, Ad-L-Fabp expression both increased the accumulation of FA and neutral lipid and also suppressed the expression of profibrogenic genes in passaged HSCs. These findings imply that the expression of L-Fabp both promotes LD accumulation and also inhibits HSC activation in vitro. The underlying mechanisms and pathways remain to be defined, but we speculate that L-Fabp aminophylline regulates the uptake and retention of lipid mediators and signaling molecules in HSCs, analogous to functions described for L-Fabp in liganding PPARα in isolated hepatocytes.24 Other studies have established a role for L-Fabp in the metabolic channeling of FA in enterocytes for complex lipid assembly.25 The findings in TFF-fed mice revealed a striking shift in LD accumulation in L-Fabp−/− mice with decreased expression of several LD-associated genes

including Plin4, Plin5, and Cidec, each of which has been shown to be modulated as downstream targets of either Pparα26 or Pparγ27, 28 in murine liver. Our a priori hypothesis, based on the role of L-Fabp in HSC activation in vitro, was that L-Fabp−/− mice would display enhanced susceptibility to high-fat diet-induced liver injury and fibrosis. Instead we found that L-Fabp−/− mice exhibited reduced fibrogenesis, which correlated with decreased hepatic steatosis. This discrepancy may reflect the complex intracellular crosstalk and lipid signaling that occurs in vivo between hepatocytes and HSCs and highlights the importance of in vivo models in understanding complex systems. Moreover, since germline deletion of L-Fabp has been shown to alter intestinal FA trafficking,12, 14, 15 it is unclear whether the absence of L-Fabp in the intestinal mucosa may also alter the progression of experimental NAFLD.