Uptake of long-chain fatty acids plays pivotal roles in metabolic homeostasis and human physiology. Uptake rates must be controlled in an organ-specific fashion to balance storage with metabolic needs during transitions between fasted and fed states. Many obesity-associated diseases, such as insulin resistance in skeletal muscle, cardiac lipotoxicity, and hepatic steatosis, are thought to be driven by the overflow of fatty acids from adipose stores and the subsequent ectopic accumulation of lipids resulting in apoptosis, ER stress, and inactivation of the insulin receptor signaling cascade. Thus, it is of critical importance to understand the components that regulate the flux of fatty acid between the different organ systems. Cellular uptake of fatty acids by key metabolic organs, including the intestine, adipose tissue, muscle, heart, and liver, has been shown to be protein mediated and various unique combinations of fatty acid transport proteins (FATPs/SLC27A1-6) are expressed by all of these tissues. Here we review our current understanding of how FATPs can contribute to normal physiology and how FATP mutations as well as hypo- and hypermorphic changes contribute to disorders ranging from cardiac lipotoxicity to hepatosteatosis and ichthyosis. Ultimately, our increasing knowledge of FATP biology has the potential to lead to the development of new diagnostic tools and treatment options for some of the most pervasive chronic human disorders.

SUMMARY Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.

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 ...

Nonshivering thermogenesis in brown adipose tissue (BAT) generates heat through the uncoupling of mitochondrial ␤-oxidation from ATP production. The principal energy source for this process is fatty acids that are either synthesized de novo in BAT or are imported from circulation. How uptake of fatty acids is mediated and regulated has remained unclear. Here, we show that fatty acid transport protein (FATP)1 is expressed on the plasma membrane of BAT and is upregulated in response to cold stimuli, concomitant with an increase in the rate of fatty acid uptake. In FATP1-null animals, basal fatty acid uptake is reduced and remains unchanged following cold exposure. As a consequence, FATP1 knockout (KO) animals display smaller lipid droplets in BAT and fail to defend their core body temperature at 4°C, despite elevated serum free fatty acid levels. Similarly, FATP1 is expressed by the BATderived cell line HIB-1B upon differentiation, and both fatty acid uptake and FATP1 protein levels are rapidly elevated following isoproterenol stimulation. Stimulation of fatty uptake by isoproterenol required both protein kinase A and mitogen-activated kinase signaling and is completely dependent on FATP1 expression, as small-hairpin RNA-mediated knock down of FATP1 abrogated the effect. Diabetes 55:3229 -3237, 2006