Fatty acid transport proteins, implications in physiology and disease - PubMed (original) (raw)
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Fatty acid transport proteins, implications in physiology and disease
Melissa Kazantzis et al. Biochim Biophys Acta. 2012 May.
Abstract
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. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
Copyright © 2011 Elsevier B.V. All rights reserved.
Figures
Figure 1
Hepatic FATP2 and FATP5 are dual-function proteins. A) Hepatic FATP2 and -5 (red circles) mediate liver fatty acid uptake and activation (yellow arrows). FATP2/5 located on microvilli (Mv) in the Space of Disse (D) mediate the uptake of fatty acids. Cytoplasmic (Cy) fatty acids are directed toward TG synthesis and storage in lipid droplets (L), toward mitochondria (M) for ß-oxidation, toward TG synthesis and LP assembly in the endoplasmic reticulum (ER) followed by LP secrection (orange arrow), or in the case of branched and very-long chain fatty acids toward peroxisomes (Per) potentially involving FATP2. Hepatic FATPs are also involved in bile acid synthesis (blue arrows), which is initiated in the ER, progresses through the Cy to M and Per where the bile acid precursor are activated by bile acid CoA synthetases, an activity associated with both FATP2 and -5. Bile acids are then secreted into bile canaliculi (BC). Deconjugated bile acids from the enterohepatic circulation are re-activated in the ER requiring the BACS activity of FATP5. FATP2 is also found on the microvili of the bile canaliculi, bile duct cells as well as the gallbladder
Figure 2
FATP’s role in disease based on gain and loss of function animal models and human studies. 1. Heart FATP1-TG causes lipotoxicity and affects diastolic function. 2. FATP1KO is protective against high-fat diet-induced insulin resistance by decreasing white adipose and muscle fat content. 3. Hepatic steatosis can be reversed by AAV-mediated FATP5 or FATP2 knock-down. 4. FATP4 loss alters fatty acid composition and disturbs the skin barrier function.
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