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Fibroblast growth factor 21

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Template:PBB Fibroblast growth factor 21 is a protein that in humans is encoded by the FGF21 gene.[1][1][2] The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.[2]

Regulation

FGF21 is specifically induced by HMGCS2 activity. The oxidized form of ketone bodies (acetoacetate) in a cultured medium also induced FGF21, possibly via a SIRT1-dependent mechanism.[3] HMGCS2 activity has also been shown to be increased by deacetylation of lysines 310, 447, and 473 via SIRT3 in the mitochondria.[4]

In mice, brown adipose tissue becomes a source of systemic FGF21 after cold exposure. Norepinephrine, acting via β-adrenergic, cAMP-mediated, mechanisms and subsequent activation of protein kinase A and p38 MAPK, induces FGF21 gene transcription and also FGF21 release in brown adipocytes. ATF2 binding to the FGF21 gene promoter mediates cAMP-dependent induction of FGF21 gene transcription. Release of FGF21 by brown fat in vivo was accompanied by a reduction in systemic FGF21 half-life.[5]

LXR represses FGF21 in humans via an LXR response element located from -37 to -22 bp on the human FGF21 promoter.[6]

Function

FGF21 stimulates glucose uptake in adipocytes but not in other cell types.[7] This effect is additive to the activity of insulin. FGF21 treatment of adipocytes is associated with phosphorylation of FRS2, a protein linking FGF receptors to the Ras/MAP kinase pathway. FGF21 injection in ob/ob mice results in an increase in Glut1 in adipose tissue. FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents.[7] Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion.[8]

Beta Klotho (KLB) functions as a cofactor essential for FGF21 activity.[9]

In cows plasma FGF21 was nearly undetectable in late pregnancy, peaked at parturition, and then stabilized at lower, chronically elevated concentrations during early lactation. Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. The liver was the major source of plasma FGF21 in early lactation with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT.[10]

Clinical Significance

Serum FGF-21 levels were significantly increased in patients with type 2 diabetes mellitus (T2DM) which may indicate a role in the pathogenesis of T2DM.[11] Elevated levels also correlate with liver fat content in non-alcoholic fatty liver disease[12] and positively correlate with BMI in humans suggesting obesity as a FGF21-resistant state.[13]

Mice lacking FGF21 fail to fully induce PGC-1alpha expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.[14]

FGF21 stimulates phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 in the liver. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of PGC-1α, but in mice PGC-1α expression was not necessary for the effect of FGF21 on glucose metabolism.[15]

In mice FGF21 is strongly induced in liver by prolonged fasting via PPARalpha and in turn induces the transcriptional coactivator PGC-1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor, playing a key role in eliciting and coordinating the adaptive starvation response. FGF21 expression is also induced in white adipose tissue by PPARgamma, which may indicate it also regulates metabolism in the fed state.[16]

Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1alpha activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an LKB1-AMPK-SIRT1-PGC1alpha-dependent mechanism in adipocytes, resulting in increased phosphorylation of AMPK, increased cellular NAD+ levels and activation of SIRT1 and deacetylation of SIRT1 targets PGC-1alpha and histone 3.[17]

References

  1. ^ a b Nishimura T, Nakatake Y, Konishi M, Itoh N (2000). "Identification of a novel FGF, FGF-21, preferentially expressed in the liver". Biochim Biophys Acta. 1492 (1): 203–6. doi:10.1016/S0167-4781(00)00067-1. PMID 10858549. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid10858549" was defined multiple times with different content (see the help page).
  2. ^ a b "Entrez Gene: FGF21 fibroblast growth factor 21".
  3. ^ Vilà-Brau A, De Sousa-Coelho AL, Mayordomo C, Haro D, Marrero PF (2011). "Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line". J. Biol. Chem. 286 (23): 20423–30. doi:10.1074/jbc.M111.235044. PMC 3121469. PMID 21502324. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  4. ^ Shimazu T, Hirschey MD, Hua L; et al. (2010). "SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production". Cell Metab. 12 (6): 654–61. doi:10.1016/j.cmet.2010.11.003. PMID 21109197. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Hondares E, Iglesias R, Giralt A; et al. (2011). "Thermogenic activation induces FGF21 expression and release in brown adipose tissue". J. Biol. Chem. 286 (15): 12983–90. doi:10.1074/jbc.M110.215889. PMC 3075644. PMID 21317437. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  6. ^ Uebanso T, Taketani Y, Yamamoto H; et al. (2011). "Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet". J. Nutr. Biochem. 23 (7): 785–90. doi:10.1016/j.jnutbio.2011.03.023. PMID 21889884. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ a b Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB (2005). "FGF-21 as a novel metabolic regulator". J. Clin. Invest. 115 (6): 1627–35. doi:10.1172/JCI23606. PMC 1088017. PMID 15902306. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A (2008). "FGF21 Corrects Obesity in Mice". Endocrinology. 149 (12): 6018–27. doi:10.1210/en.2008-0816. PMID 18687777. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M (2007). "βKlotho is required for metabolic activity of fibroblast growth factor 21". Proc. Natl. Acad. Sci. U.S.A. 104 (18): 7432–7. doi:10.1073/pnas.0701600104. PMC 1855074. PMID 17452648. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Schoenberg KM, Giesy SL, Harvatine KJ; et al. (2011). "Plasma FGF21 Is Elevated by the Intense Lipid Mobilization of Lactation". Endocrinology. 152 (12): 4652–61. doi:10.1210/en.2011-1425. PMID 21990311. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Cheng X, Zhu B, Jiang F, Fan H (2011). "Serum FGF-21 levels in type 2 diabetic patients". Endocr. Res. 36 (4): 142–8. doi:10.3109/07435800.2011.558550. PMID 21973233.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Yan H, Xia M, Chang X; et al. (2011). "Circulating fibroblast growth factor 21 levels are closely associated with hepatic fat content: a cross-sectional study". PLoS ONE. 6 (9): e24895. doi:10.1371/journal.pone.0024895. PMC 3174975. PMID 21949781. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  13. ^ Kralisch S, Fasshauer M (2011). "Fibroblast growth factor 21: effects on carbohydrate and lipid metabolism in health and disease". Curr Opin Clin Nutr Metab Care. 14 (4): 354–9. doi:10.1097/MCO.0b013e328346a326. PMID 21505329. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ Potthoff MJ, Inagaki T, Satapati S; et al. (2009). "FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response". Proc. Natl. Acad. Sci. U.S.A. 106 (26): 10853–8. doi:10.1073/pnas.0904187106. PMC 2705613. PMID 19541642. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Fisher FM, Estall JL, Adams AC; et al. (2011). "Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo". Endocrinology. 152 (8): 2996–3004. doi:10.1210/en.2011-0281. PMC 3138239. PMID 21712364. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Kliewer SA, Mangelsdorf DJ (2010). "Fibroblast growth factor 21: from pharmacology to physiology". Am. J. Clin. Nutr. 91 (1): 254S–257S. doi:10.3945/ajcn.2009.28449B. PMC 2793111. PMID 19906798. {{cite journal}}: Unknown parameter |month= ignored (help)
  17. ^ Chau MD, Gao J, Yang Q, Wu Z, Gromada J (2010). "Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway". Proc. Natl. Acad. Sci. U.S.A. 107 (28): 12553–8. doi:10.1073/pnas.1006962107. PMC 2906565. PMID 20616029. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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