The fibroblast growth factor (FGF) superfamily includes 22 secreted proteins that all participate in heparan sulfate (HS)-dependent signaling through a group of four FGF receptors and their splice variants. Except for one subfamily, all FGFs exhibit high-affinity binding to heparans and HS, and thus exert paracrine control in areas adjacent to their secretion. Only the FGF-19 subfamily, including FGF-21, FGF-23, and FGF-19 in humans and the mouse FGF-19 equivalent, FGF-15, acts in an endocrine fashion.1 Although they also are dependent on HS for signaling, they bind these molecules with low affinity and are thus able to circulate more freely than other FGFs. Since they and their FGF receptors are broadly present, tissue specificity of their actions has been somewhat of a mystery. However, recent studies provide a possible explanation. Each of these FGF-19 family members has been shown to require cofactors from the Klotho family of transmembrane proteins. Klotho proteins effectively convert the interacting FGF receptors to receptors specific for select FGF-19 members.1, 2, 3
Klotho proteins appear to coordinate the complex of HS and FGF Rs with FGF-19 members to provide tissue specificity to these interactions.1 For example, FGF-19 is produced by intestinal epithelia in response to food intake but has its activity in the liver where both Klotho-beta and FGF R4 are expressed. There it completes a feedback loop to downregulate two key genes in the bile acid synthase pathway, cholesterol 7 alpha-hydroxylase (Cyp7a1) and sterol 12alpha-hydroxylase (Cyp8b1).3, 4, 5 Similarly, FGF-23, while produced in the bone, acts instead on Klotho- and FGF R1c-expressing kidney cells. This interaction enables FGF-23 to have a profound negative regulatory effect on 1 alpha-hydroxylase, the rate-limiting enzyme in the synthesis of 1,25(OH)2D3 (vitamin D), and thus affect calcium and phosphorus homeostasis.2, 6 While FGF-21 and Klotho-beta are both expressed in the liver, expression of Klotho-beta with FGF R1c in adipose tissue instead confers FGF-21 activity there. Its action in adipocytes enhances production of the GLUT1 transporter, stimulating lipolysis and glucose uptake in the fasting state.3, 7
||Klotho family members increase the affinity of FGF-19 family members for their receptor/heparan sulfate combination. Limited expression and combination of Klothos and FGF receptors allows tissue specificity of FGF activity.
The effect of Klotho proteins on energy metabolism and aging is a fascinating and still unfolding story. Because its disruption produces a premature aging-like syndrome, Klotho is named for a Greek goddess, one of the three Fates, who "spins the thread of life".8 By mechanisms not entirely understood, the aging symptoms of Klotho-deficient mice can be partially ameliorated by restoring negative control over systemic vitamin D activity.2 Klotho-beta may also participate in the control of aging by acting as a cofactor to mediate the key effects of FGF-21 on metabolic changes occurring during calorie restriction, a phenomenon known to prolong lifespan.9 Klotho participates in other anti-aging activities that may or may not involve FGF-19 family members. It downregulates insulin and IGF signaling and increases endothelial cell resistance to oxidative stress, both of which may also contribute to longevity.10,11 Recently, Klotho has been identified as a Wnt antagonist that potentially limits Wnt-mediated cellular senescence.12 Some of these effects appear to involve interaction of proteolytically released, soluble Klotho with a receptor yet to be identified.10, 11, 12
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