Findings from knockout mice suggest that most BI-D1870 insulin responses associated with nutrient homeostasis are mediated through IRS-1 and/or IRS-2. IRS-1 is induced in high insulin conditions including the post-prandial state and obesity, whereas IRS-2 is increased in low insulin states such as fasting and caloric restriction. This information, together with the understanding that both high and low insulin states also trigger liver lipid accumulation, begs the question as to whether the relative level of insulin and its concomitant IRS signaling is causally related to the accumulation of lipids in the liver. To address this question, we focused on fatty acid transport proteins as downstream targets of IRS signaling, since these molecules putatively transport free fatty acids into the cell and are therefore likely intermediaries of hepatic steatosis. Further, FATPs are not exclusively plasma membrane bound and are also found to increase fatty acid transport when present intra-cellularly including on the endoplasmic reticulum and some data suggest that at least in adipocytes FATP1 may translocate to the cell surface from an intracellular perinuclear compartment upon insulin stimulation. Of the various FATPs, FATP5 is found exclusively in the liver, while FATP-2 is found in liver and kidney. Deletion of either FATP-2 or FATP-5 in mice results in decreased hepatic steatosis. In addition, these transporters are up-regulated in the livers of patients with NAFLD. Our overarching hypothesis was that high or low of insulin concentration may trigger the IRS-1 or 2 signaling and consequently activate FATP-2 & 5 mediated fatty acid transport, thus contributing to hepatic lipid accumulation. Our in vivo models of hepatic steatosis with perturbed insulin concentrations had relatively increased IRS-1 expression at high insulin concentrations, and relatively increased IRS-2 at low insulin concentrations. This relative ‘imbalance’ between the two IRS molecules was associated with an up-regulation of FATP-2 & 5 in both states. Holding other parameters constant in vitro, we replicated this bimodal TG accumulation function simply by varying insulin levels. We thus describe a novel insulin driven bimodal FATP-lipid accumulation response. FATP was first identified in 1994 by Schaffer et al and shown to increase the uptake of long chain fatty acids across the plasma membrane. The murine Fatp1 gene was found to span approximately 16 kilobases and contain 13 exons, of which exon 2 was shown to be alternatively spliced. Since then multiple groups have worked on various isoforms of FATP in different tissues of interest. Further, human relevance has been described and researched in the setting of X-linked adrenoleukodystrophy, a genetic neurodegenerative disorder wherein increased levels of saturated very long-chain fatty acids are found in tissues and plasma. Herein FATP2 has independently been identified as a hepatic peroxisomal very long-chain acyl-CoA synthetase. Further, in adipocytes FATP1 has been shown to be transcriptionaly regulated by insulin.