Fatty acid-binding protein

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Structure of one of the FABP proteins (FABP3) known as Heart-type fatty acid binding protein. Protein FABP3 PDB 1g5w.png
Structure of one of the FABP proteins (FABP3) known as Heart-type fatty acid binding protein.

The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. [1] [2] These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. [3] Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. [4] The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) are also discovered to bind human FABPs (1, 3, 5, and 7) that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. [5] Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. [6] Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity. [7]

Contents

Fatty Acid Binding Proteins (FABPs) represent a family of proteins that play a pivotal role in cellular lipid metabolism. These proteins act as intracellular carriers, facilitating the transport and utilization of fatty acids within cells. With their diverse tissue-specific distribution and involvement in various cellular processes, FABPs contribute significantly to energy homeostasis, lipid metabolism, and even cellular signaling. Fatty acid-binding proteins (FABPs) are members of the intracellular lipid-binding protein (iLBP) family and are involved in reversibly binding intracellular hydrophobic ligands and trafficking them throughout cellular compartments, including the peroxisomes, mitochondria, endoplasmic reticulum and nucleus. [2] This comprehensive exploration aims to delve into the structure, function, types, and implications of FABPs in health and disease.

Structure

FABPs are small, structurally conserved cytosolic proteins consisting of a water-filled, interior-binding pocket surrounded by ten anti-parallel beta sheets, forming a beta barrel. At the superior surface, two alpha-helices cap the pocket and are thought to regulate binding. FABPs have broad specificity, including the ability to bind long-chain (C16-C20) fatty acids, eicosanoids, bile salts and peroxisome proliferators. FABPs demonstrate strong evolutionary conservation and are present in a spectrum of species including Drosophila melanogaster, Caenorhabditis elegans, mouse and human. The human genome consists of nine putatively functional protein-coding FABP genes. The most recently identified family member, FABP12, has been less studied. [2]

Function

Dictated by the characteristic structure, the main function of the FABPs is to bind fatty acids, as well as the intake, transportation and consumption, despite their different selectivity, affinity, and binding mechanism. [8] They enhance the solubility of hydrophobic fatty acids, allowing their efficient transport within the aqueous cytoplasm. FABPs also participate in the uptake of fatty acids from the extracellular environment and their subsequent delivery to specific cellular compartments, such as the nucleus, mitochondria, or endoplasmic reticulum. Research emerging in the last decade has suggested that FABPs have tissue-specific functions that reflect tissue-specific aspects of lipid and fatty acid metabolism. Proposed roles for FABPs include assimilation of dietary lipids in the intestine, targeting of liver lipids to catabolic and anabolic pathways, regulation of lipid storage and lipid-mediated gene expression in adipose tissue and macrophages, fatty acid targeting to β-oxidation pathways in muscle, and maintenance of phospholipid membranes in neural tissues. [8]

FABPs facilitate the transport of fatty acids by forming a complex with them. This complex shields the hydrophobic fatty acids from the surrounding aqueous environment, enabling their transit through the cytoplasm. Different types of FABPs exhibit tissue-specific expression, ensuring the efficient transport of fatty acids to locations where they are needed most for various cellular processes. Studies have reported that the intracellular trafficking of fatty acids is a complicated and dynamic process that directly or indirectly influences multiple functions of the cell and especially regulates important biochemical processes in normal cells, [9] including gene expression modulation, cell development, metabolism, and inflammatory response through enzymatic and transcriptional networks. [10]

Cellular signaling

Beyond their role in fatty acid transport, FABPs also participate in cellular signaling pathways. By transporting fatty acids to the nucleus, FABPs can modulate the activity of nuclear receptors involved in transcriptional regulation. This interaction can influence gene expression, contributing to the overall regulation of cellular processes, including those related to lipid metabolism.

Role in metabolism

FABPs are integral to lipid metabolism, participating in various processes that contribute to energy homeostasis. These include fatty acid uptake, storage, and oxidation. In adipocytes, A-FABP is involved in the storage of fatty acids as triglycerides, while in the liver, L-FABP contributes to the regulation of lipid metabolism and cholesterol homeostasis. Metabolic syndromes such as obesity, high uric acid, high blood fat, hypertension, type II diabetes, and atherosclerosis, have received increasing attention due to the great changes that have occurred in eating habits and the general lifestyle. Accumulating evidence shows that the level of FABP5 may be closely associated with the pathogenesis of chronic metabolic diseases through its expression in adipocytes and macrophages. [11]

Types

Several distinct types of FABPs have been identified, each exhibiting a tissue-specific distribution. Some prominent examples include:

Each type of FABP has a specific role in the metabolism and utilization of fatty acids within its respective tissue, highlighting the functional diversity of this protein family.

Clinical significance

Dysregulation of FABPs has been implicated in various metabolic disorders, providing insights into potential therapeutic targets. In obesity, for instance, there is often an altered expression of FABPs in adipose tissue, contributing to abnormal lipid metabolism. It has recently been suggested that macrophage accumulation in adipose tissue is a feature of adipose tissue inflammatory responses triggered by obesity and hence may contribute to the metabolic consequences such as insulin resistance. [12] In diabetes, FABPs may influence insulin sensitivity and glucose metabolism. Additionally, in cardiovascular diseases, the dysregulation of FABPs in the heart and blood vessels may impact fatty acid utilization and contribute to pathological conditions.

Understanding the specific roles of FABPs in disease states is an active area of research, with potential implications for the development of targeted therapies. Modulating FABP activity or expression could offer new avenues for intervention in conditions associated with aberrant lipid metabolism. The creation of pharmacological agents to modify FABP function may therefore provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, thus offering a new class of multi-indication therapeutic agents. [13]

Medical applications

Fatty Acid Binding Proteins (FABPs) have shown significant promise in various medical applications due to their role in cellular lipid metabolism and their involvement in several physiological processes. Key medical applications of FABPs include:

Biomarkers for disease diagnosis and prognosis

Cardiovascular Diseases: Elevated levels of FABPs, particularly heart-type FABP (H-FABP), in blood plasma have been associated with acute myocardial infarction. Measurement of FABPs can aid in the early diagnosis and prognosis of cardiovascular events. Liver Diseases: Liver-type FABP (L-FABP) has been studied as a potential biomarker for liver diseases such as non-alcoholic fatty liver disease (NAFLD) and liver cirrhosis. Monitoring L-FABP levels can provide insights into liver function and pathology.

Monitoring and predicting metabolic disorders

Obesity and Diabetes: FABPs, especially adipocyte FABP (A-FABP), are linked to obesity and insulin resistance. Monitoring FABP levels can provide information about the metabolic status of individuals, and targeting FABPs may offer therapeutic strategies for managing obesity-related complications. Type 2 Diabetes: FABPs are implicated in insulin resistance. Studying their expression and function can contribute to a better understanding of the mechanisms underlying type 2 diabetes, potentially leading to the development of targeted therapies.

Drug development and therapeutics

Target for Drug Intervention: FABPs are considered potential targets for drug development. Modulating FABP activity could be a strategy to regulate lipid metabolism and address conditions like atherosclerosis, metabolic syndrome, and other disorders associated with abnormal fatty acid handling. Anti-Inflammatory Therapies: FABPs are involved in inflammatory responses, and targeting them could be a therapeutic approach for inflammatory conditions. For example, inhibition of FABPs might attenuate inflammation associated with certain diseases.

Neurological disorders

Alzheimer's Disease: FABPs, particularly FABP7, have been implicated in neurodegenerative diseases such as Alzheimer's. Understanding their role in brain lipid metabolism may provide insights into disease mechanisms and potential therapeutic targets. Neuroprotection: Some studies suggest that FABPs, especially brain-type FABP (B-FABP), may play a neuroprotective role. Modulating their expression or activity could be explored as a strategy for neuroprotection in conditions like stroke.

Cancer research

Prognostic Markers: Altered expression of certain FABPs has been observed in various cancers. They may serve as prognostic markers, and understanding their role in cancer cell metabolism could open avenues for targeted therapies. Drug Delivery: FABPs have been explored for their potential in targeted drug delivery to cancer cells. Conjugating therapeutic agents with molecules that bind to FABPs may enhance drug delivery to cancer cells expressing these proteins.

Inflammatory bowel disease (IBD)

Biomarkers for IBD: FABPs, including intestinal FABP (I-FABP), have been investigated as potential biomarkers for inflammatory bowel diseases. Elevated levels in serum may indicate intestinal mucosal damage.

Wound Healing and Tissue Repair

Regeneration and Repair: FABPs, such as epidermal FABP (E-FABP), are expressed in skin cells and may play a role in skin regeneration and wound healing. Understanding their functions could contribute to strategies for enhancing tissue repair.

Family members

Members of this family include:

Protein nameGeneTissue distributionComment
FABP 1 FABP1 liver
FABP 2 FABP2 intestinal
FABP 3 FABP3 muscle and heartmammary-derived growth inhibitor
FABP 4 FABP4 adipocyte
FABP 5 FABP5 epidermalpsoriasis-associated
FABP 6 FABP6 ilealgastrotropin
FABP 7 FABP7 brain
FABP 8 PMP2 peripheral nervous systemperipheral myelin protein 2
FABP 9 FABP9
FABP 11fabp11restricted to fishes
FABP 12 FABP12 presence shown in human retinoblastoma cell lines, rodent retina and testis. [14]

Pseudogenes

PseudogeneComment
FABP3P2
FABP5P1
FABP5P2
FABP5P3
FABP5P4
FABP5P5
FABP5P6
FABP5P7
FABP5P8
FABP5P9
FABP5P10
FABP5P11
FABP5P12
FABP5P13
FABP5P14
FABP5P15
FABP7P1
FABP7P2
FABP12P1

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<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

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<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

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References

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