Klotho (biology)

Klotho is an enzyme that in humans is encoded by the KL gene.[5] There are three subfamilies of klotho: α-klotho, β-klotho, and γ-klotho.[6] α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21.[7] When the subfamily is not specified, the word "klotho" generally means the α-klotho subfamily.[8]

KL
Identifiers
AliasesKL, entrez:9365, klotho, HFTC3
External IDsOMIM: 604824 MGI: 1101771 HomoloGene: 68415 GeneCards: KL
Gene location (Human)
Chr.Chromosome 13 (human)[1]
Band13q13.1Start33,016,423 bp[1]
End33,066,143 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

9365

16591

Ensembl

ENSG00000133116

ENSMUSG00000058488

UniProt

Q9UEF7

O35082

RefSeq (mRNA)

NM_004795
NM_153683

NM_013823

RefSeq (protein)

NP_004786

NP_038851

Location (UCSC)Chr 13: 33.02 – 33.07 MbChr 5: 150.95 – 150.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form.[9] Proteases can convert the membrane-bound form into the circulating form.[10]

The KL gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic kidney failure (CKF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CKF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[11][12] Transgenic mice that overexpress Klotho live longer than wild-type mice.[13]

Function

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Makoto Kuro-o et al.[14] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[15][16] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[17]

The binding of certain fibroblast growth factors (FGF's, viz., FGF19 and FGF21) to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.[18][19]

α-klotho changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 (decreasing phosphate reabsorption in the kidney) and decreasing that of TRPC6 (decreasing phosphate absorption from the intestine).[20] α-klotho increases kidney calcium reabsorption by stabilizing TPRV5.[21]

Clinical significance

α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis.[8] Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction.[22]

β-klotho activation of FGF21 protein has a protective effect on heart muscle cells.[23] Obesity is characterized by FGF21 resistance, believed to be caused by the inhibition of β-klotho by the inflammatory cell signalling protein (cytokine) tumor necrosis factor alpha.[23]

Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects.[24] Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory.[25]

It has been found that the decreased Klotho expression may be due to DNA hypermethylation, which may have been induced by the overexpression of DNMT3a.[26] Klotho may be a reliable gene for early detection of methylation changes in oral tissues, and can be used as a target for therapeutic modification in oral cancer during the early stages.

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Effects on aging

Mice lacking either fibroblast growth factor 23 or the α-klotho enzyme display premature aging due to hyperphosphatemia.[27] Many of these symptoms can be alleviated by feeding the mice a low phosphate diet.[7]

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[13] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[28]

Klotho increases membrane expression of the inward rectifier ATP-dependent potassium channel ROMK.[20] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[29][30][31][32]

Klotho is an antagonist of the Wnt signaling pathway, and chronic Wnt stimulation can lead to stem cell depletion and aging.[33]

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References
  1. GRCh38: Ensembl release 89: ENSG00000133116 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000058488 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (Jan 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochemical and Biophysical Research Communications. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267.
  6. Dolegowska K, Marchelek-Mysliwiec M, Nowosiad-Magda M, Slawinski M, Dolegowska B (2019). "FGF19 subfamily members: FGF19 and FGF21". Journal of Physiology and Biochemistry. 75 (2): 229–240. doi:10.1007/s13105-019-00675-7. PMC 6611749. PMID 30927227.
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  11. "Entrez Gene: klotho".
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Further reading

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