FA2H

Official Full Name

fatty acid 2-hydroxylase

Organism

Homo sapiens

GeneID

79152

Background

This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.[provided by RefSeq, Mar 2010]

Synonyms

FAAH; FAH1; SCS7; SPG35; FAXDC1;

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Detailed Information

Fatty acid metabolism is an important life process that guarantees the normal operation of various tissues and cells in the organism. The main pathway of fatty acid catabolism is β-oxidation, but there is another metabolic pathway of α-oxidation for fatty acids. Fatty acid 2-hydroxylase (Fa2h) catalyzes the α-oxidation reaction of fatty acids and hydroxylates the C-2 position of fatty acids to produce 2-hydroxy fatty acids. Fa2h is highly expressed in brain, skin, colorectal, and gastric tissues. It plays an important role in maintaining the normal function of the nervous system, proliferating tumor cells, and chemotherapeutic drug sensitivity.

Physiological Function

Fa2h can catalyze the production of 2-hydroxy fatty acids from linear fatty acids, which is considered to be the initial step of α-oxidation of linear fatty acids. Sphingolipids, an important component of cell membrane lipid rafts, are rich in 2-hydroxy fatty acids. When Fa2h in the cell is knocked down, the lateral fluidity of lipids on lipid rafts increases. Changes in lipid membrane fluidity will also affect the content of certain membrane proteins. When Fa2h is a deletion, the co-localization of GLUT4, an important protein involved in glucose uptake, with lysosomal LAMP1 increases. The degradation of GLUT4 by lysosomes causes its content to decrease and glucose uptake also decreases. Reduced glucose intake limits the source of lipid synthesis raw materials, and the expression response of synthesis-related proteins is down-regulated, which ultimately leads to the inhibition of intracellular lipid production. Also, the expression levels of insulin receptor substrate (IRS) and two important proteins involved in lipid synthesis, SCD1, and FAS, were significantly decreased. During the differentiation process of 3T3-L1 preadipocytes, Fa2h mRNA levels continued to increase. After Fa2h specific siRNA knocked down Fa2h expression, the mRNA levels of differentiation marker proteins such as PPAB, CD36, SCD1, and intracellular triglycerides were all in significant decline, which indicates that Fa2h can not only control lipid differentiation but also is necessary for this process.

Fa2h and Hippo Signaling Pathway

Figure 1. Schematic overview of Hippo pathway. (Salem et al. 2019)

Fa2h and Disease

Fatty acid 2-hydroxylase can catalyze fatty acids to form 2-hydroxylated fatty acids, and then through acetyl-CoA synthase, ceramide synthase, and dihydrosphingosine form dihydroceramide, which is formed under the action of decorating enzyme Hydroxylated ceramide. In many cells, hydroxylated ceramide accounts for 1-3% of the total ceramide, but it accounts for about 50% in creeping keratinocytes or rectal epidermal cells. It is the precursor for the formation of various hydroxylated sphingolipids. Sphingolipids are an important part of the myelin sheath, and hydroxylated sphingolipids are abundant in the myelin sheath of neurogenic cells. The deletion and mutation of Fa2h lead to changes in the content of hydroxylated sphingolipids in the myelin sheaths of neuronal cells, leading to neurological disorders, degenerative neurological diseases, and genetic spastic paralysis. Mutations in the Fa2h gene have been thought to be related to leukoencephalopathy, SPG35 type, and neurodegenerative diseases of iron deposits in brain tissue. Besides, hydroxylated sphingolipids play an important role in the development and stability of myelin and axons. The cell surface antigens of cancer cells are usually expressed in a field, and glycosylated sphingolipids are the first to be reported as tumor-related cell surface antigens. It can cause abnormal proliferation and migration of tumor cells. Glycosylated sphingolipids, which are abnormally highly expressed in some human tumor cells, contain a large amount of hydroxylated fatty acids, which can lead to ovarian cancer, glioma cells, lung small cell carcinoma, colon and liver cancer.

References:

Salem, O., and Hansen, C. G. (2019). 'The Hippo Pathway in Prostate Cancer', Cells, 8(4), 370.
Mizutani, Y., Kihara, A., Chiba, H., Tojo, H., and Igarashi, Y. (2008). '2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length'. Journal of lipid research, 49(11), 2356–2364.
Kruer, M. C., Paisán-Ruiz, C., Boddaert, N., Yoon, M. Y., Hama, H., Gregory, A., Malandrini, A., Woltjer, R. L., Munnich, A., Gobin, S., Polster, B. J., Palmeri, S., Edvardson, S., Hardy, J., Houlden, H., and Hayflick, S. J. (2010). 'Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)'. Annals of neurology, 68(5), 611–618.
Hama H. (2010). 'Fatty acid 2-Hydroxylation in mammalian sphingolipid biology'. Biochimica et biophysica acta, 1801(4), 405–414.

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