Role of Fatty Acid Binding Proteins and Long Chain Fatty Acids in Modulating Nuclear Receptors and Gene Transcription

Abstract

Abnormal energy regulation may significantly contribute to the pathogenesis of obesity, diabetes mellitus, cardiovascular disease, and cancer. For rapid control of energy homeostasis, allosteric and posttranslational events activate or alter activity of key metabolic enzymes. For longer impact, transcriptional regulation is more effective, especially in response to nutrients such as long chain fatty acids (LCFA). Recent advances provide insights into how poorly water-soluble lipid nutrients [LCFA; retinoic acid (RA)] and their metabolites (long chain fatty acyl Coenzyme A, LCFA-CoA) reach nuclei, bind their cognate ligand-activated receptors, and regulate transcription for signaling lipid and glucose catabolism or storage: (i) while serum and cytoplasmic LCFA levels are in the 200 mircroM-mM range, real-time imaging recently revealed that LCFA and LCFA-CoA are also located within nuclei (nM range); (ii) sensitive fluorescence binding assays show that LCFA-activated nuclear receptors [peroxisome proliferator-activated receptor-alpha (PPARalpha) and hepatocyte nuclear factor 4alpha (HNF4alpha)] exhibit high affinity (low nM KdS) for LCFA (PPARalpha) and/or LCFA-CoA (PPARalpha, HNF4alpha)-in the same range as nuclear levels of these ligands; (iii) live and fixed cell immunolabeling and imaging revealed that some cytoplasmic lipid binding proteins [liver fatty acid binding protein (L-FABP), acyl CoA binding protein (ACBP), cellular retinoic acid binding protein-2 (CRABP-2)] enter nuclei, bind nuclear receptors (PPARalpha, HNF4alpha, CRABP-2), and activate transcription of genes in fatty acid and glucose metabolism; and (iv) studies with gene ablated mice provided physiological relevance of LCFA and LCFA-CoA binding proteins in nuclear signaling. This led to the hypothesis that cytoplasmic lipid binding proteins transfer and channel lipidic ligands into nuclei for initiating nuclear receptor transcriptional activity to provide new lipid nutrient signaling pathways that affect lipid and glucose catabolism and storage.

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

“…Our findings, which are in agreement with other studies showing that intracellular lipids pools and fatty acid trafficking have a regulatory role in lipid metabolism through transcriptional regulation (1,51,52), suggest that ACSL3 may have an integral role in regulating lipogenesis and, potentially, the development of hepatic steatosis and its co-morbidities.…”

Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice

“…However, in the absence of MTP, triglyceride hydrolysis and synthesis may be maximal, and FFA flux might be higher than the capacity of triglyceridesynthesizing enzymes, leading to accumulation of FFA in cells. FFA would then interact with fatty acid-binding protein and be transported to the nucleus to increase expression of genes (39) involved in fatty acid transport, e.g. L-FABP, and oxidation such as PPAR␣ and PPAR␥.…”

“…ABCA1 is a membrane bound protein that modulates membrane raft domains (39,41). Hence, it is possible that ABCA1 could sequester FFA in lipid rafts (42) making them inaccessible to ␤-oxidation.…”

Association of FABP5 Expression With Poor Survival in Triple-Negative Breast Cancer

“…15 PUFAs and RA play important roles in gene regulation in both normal and cancer cells by binding and activating their corresponding nuclear receptors, peroxisome proliferator-activated receptors (PPARs), retinoic acid receptors (RARs), or retinoid X receptors (RXRs). 16,17 Because PUFAs and RA are hydrophobic molecules, their cellular uptake, transportation, metabolism, and nuclear translocation (as well as interaction with their nuclear receptors) must be facilitated by their corresponding intracellular lipid-binding proteins. To date, at least 17 intracellular lipid-binding proteins, including fatty acid-binding proteins (FABPs), cellular retinol-binding proteins (CRBPs), and cellular retinoic acid-binding proteins (CRABPs) have been identified in vertebrates.…”