Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected. Moreover, loss of FATP1 function altered regulation of postprandial serum LCFA, causing a redistribution of lipids from adipocyte tissue and muscle to the liver, and led to a complete protection from diet-induced obesity and insulin desensitization. This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids. The strong protection against diet-induced obesity and insulin desensitization observed in FATP1-null animals suggests FATP1 as a novel antidiabetic target.

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Here we address whether FATP2 is 1) a peroxisomal enzyme, 2) a plasma membrane-associated long-chain fatty acid (LCFA) transporter, or 3) a multifunctional protein. We found that, in mouse livers, only a minor fraction of FATP2 localizes to peroxisomes, where it contributes to approximately half of the peroxisomal VLACS activity. However, total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake. This suggests FATP2 as a potential target for a therapeutic intervention of hepatosteatosis. Adeno-associated virus 8-based short hairpin RNA expression vectors were used to achieve liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding, concomitant with improvements in liver physiology, fasting glucose, and insulin levels. Based on our findings, we propose a model in which FATP2 is a multifunctional protein that shows subcellular localization-dependent activity and is a major contributor to peroxisomal

CSH is associated with a significantly increased risk of infection requiring hospitalization within 1 year following cardiac implantable electronic device surgery. Strategies aimed at reducing hematomas may decrease the long-term risk of infection. (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial [BRUISE CONTROL]; NCT00800137).

Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease.The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) 2 is presently estimated at 30% of the general population and affects a majority of patients with obesity and type 2 diabetes (1, 2). In obese individuals, chronically elevated serum free fatty acids (FFAs) and high insulin levels lead to both increased FFA uptake by the liver and increased synthesis of lipids, resulting in hepatic triglycerides (TG) accumulation, typically accompanied by hepatic insulin desensitization (1, 3) involving protein kinase C ⑀ (3). Current pharmacological treatment strategies for NAFLD focus principally on increasing hepatic fatty acid oxidation (4) and improving extrahepatic insulin sensitivity (5). However, none of these treatment methods reduce hepatic uptake of dietary fats, and novel therapeutics that specifically aim at reversing NAFLD in the context of obesity would be highly desirable.Based on the premises that obesity-associated NAFLD is primarily driven by the continuous protein-mediated uptake of fatty acids by the liver and that NAFLD is a contributing factor to whole-body insulin desensitization, we argued that blocking proteins responsible for hepatic fatty acid uptake should prevent or reverse hepatic steatosis, thus improving insulin sensitivity and glucose homeostasis. Two members of the fatty acid transport protein (FATP) family, FATP2 and FATP5, are robustly expressed in liver (6) and are thought to be involved in the early steps of long-chain fatty acid uptake/activation (7,8). We recently demonstrated the importance of FATP5 in hepatic lipid metabolism by showing that deletion of FATP5 partially protected mice from developing high fat diet-induced obesity and improved insulin-sensitivity (9, 10).To explore the consequences of hepatic FATP5 ablation ...