FABP3

Official Full Name

fatty acid binding protein 3

Organism

Homo sapiens

GeneID

2170

Background

The intracellular fatty acid-binding proteins (FABPs) belongs to a multigene family. FABPs are divided into at least three distinct types, namely the hepatic-, intestinal- and cardiac-type. They form 14-15 kDa proteins and are thought to participate in the uptake, intracellular metabolism and/or transport of long-chain fatty acids. They may also be responsible in the modulation of cell growth and proliferation. Fatty acid-binding protein 3 gene contains four exons and its function is to arrest growth of mammary epithelial cells. This gene is a candidate tumor suppressor gene for human breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Synonyms

MDGI; FABP11; H-FABP; M-FABP; O-FABP;

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Detailed Information

Fatty acid binding protein (FABP) is a hydrophobic ligands affiliative protein at the size of 14-15 kDa, constituted by nine members with tissue-specific expression patterns. Among those FABP members, FABP4 and FABP5 have been studied a lot. High expression of FABP4/5 in adipose tissue and macrophages contributed to the occurrence of metabolic diseases like adipose inflammation and insulin resistance. Monounsaturated fatty acid production induced by stearoyl-CoA desaturase1 (SCD-1) upregulation in macrophage FABP4 absent mice was found to be a prevention for atherosclerosis. Moreover, higher tolerance to fatty-rich dietary induced obesity, insulin resistance, and diabetes was found in Fabp4/5 double-deficient mice. FABP3 is highly expressed in heart and skeletal muscles, and elevated expression in skeletal muscles exhibits after consumption of a high fat diet. FABP3 partially deficient mice were reported to perform down-regulated fatty acid recycle rate. So FABP3 is regarded as lipid 'chaperone' responsible for regulating solubility, mobility, and utilization of fatty acids.

FABP-3 acts as a valuable target for sarcopenia

Proteomic analysis revealed that FABP3 is highly expressed in aged muscle. However, how FABP3 functions to promote muscle ageing remains to be an unsolved problem. Sarcopenia is defined by loss of muscle mass and function in aged skeletal muscle, series of unfavorable consequences including falls, fractures, frailty, and mortality in the elderly may be caused by it. Seung-Min Lee confirmed an age-dominated FABP3 abundance alteration signature by comparative lipidomic analyses in young versus aged muscle, and in FABP3-overexpressing or knockdown muscle. Analyzing whether lipid composition affects membrane fluidity or not by fluorescence recovery after photobleaching (FRAP) analysis for myotubes, for the purpose of assessing how FABP3-mediated downstream signaling shapes muscle mass and contractility, thus putting forward a new mechanism for skeletal muscle aging. It is reported that upregulation of FABP3 in aged skeletal muscles disrupt innate homeostasis via reshaping lipid composition, lipidomic analyses revealed upregulation of FABP3 alters the membrane lipid composition to that of aged one by cutting down polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and Lys phosphatidylcholine. FABP3-reliant membrane lipid alterations inhibit protein synthesis to constrain muscle recovery through PERK-elF2α invited ER stress. Knockdown of FABP3 may reverse the phenomenon of ER induced muscle recovery constraint. So FABP-3 may act as a valuable target for sarcopenia for its driving force onto membrane lipid composition-mediated ER stress to regulate muscle homeostasis.

Cardiac hypertrophy and heart failure exacerbated by FABP3 deficiency

The advanced genomic technology, single-cell RNA sequencing (scRNA-seq), was used to reveal that significant transcriptional differences in cellular metabolism act as the most profound contributor to cardiac dysfunction. Specifically, the shift from fatty acid β-oxidation (FAO) to glucose metabolism of energy preference accompanied with upregulation of FAO genes and downregulation glucose oxidation genes in the described pathophysiological conditions, such as hypertrophy and heart failure. There has been reported that glucose consumption increase may induce cardiac hypertrophy while myocardial energetics and cardiac function can be improved by preservation of FAO. Occupation of nearly 70% ATP production by fatty acid β-oxidation emphasized the crucial role fatty acid metabolism plays in heart function maintenance. Unlike glucose, the insolubility of fatty acid makes it difficult to transport for utilization unless binding to lipid chaperones. FABP3 is a widely distributed little protein involved in cell metabolism via binding to free long-chain fatty acids (LAFAs), thus preventing lipid accumulation from inducing toxicity, in addition to this, the cellular and circulating levels of FABP3 showed a positive relationship with cardiac hypertrophy in patients and mice in the context of cardiac hypertrophy.

Fig 1. Schematic demonstration of FABP3-mediated PPARα pathway references in cardiac metabolic reprogramming regulation (Chen et al. 2021)

References:

Seung-Min Lee, Seol Hee Lee, Youngae Jung. (2020) 'FABP3-mediated membrane lipid saturation alters flfluidity and induces ER stress in skeletal muscle with aging', Nature Communication, doi: 10.1038/s41467-020-19501-6.
Nakamura M, Sadoshima J. (2018) 'Mechanisms of physiological and pathological cardiac hypertrophy', Nat Rev Cardiol, doi: 10.1038/s41569-018-0007-y.
Lingfang Zhuang, Ye Mao, Zizhu Liu. (2021) 'FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway'. Frontiers in Cardiovascular Medicine, doi: 10.3389/fcvm.2021.722908.

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