藥學(xué)專業(yè)畢業(yè)論文外文翻譯--成纖維細(xì)胞生長(zhǎng)因子-22作為一個(gè)代謝性疾病治療劑（英文）

1、Biodrugs 2008; 22 (1): 37-44 NOVEL THERAPEUTIC STRATEGIES 1173-8804/08/0001-0037/$48.00/0© 2008 Adis Data Information BV. All rights reserved.Fibroblast Growth Factor-21 as a Therapeutic Agent for Metabolic Diseases

2、Alexei Kharitonenkov and Armen B. ShanafeltBioTechology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USAContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . .

3、. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371. The Role of Fibroblast Growth Factors (

4、FGFs) in the Regulation of Metabolic Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372. Overview of FGF21 and its In Vitro Effects . . . . . . . . . . . . . . . . . . . . . . . . .

5、 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383. FGF21 In Vivo Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6、 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394. Insights into FGF21 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7、. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8、. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Fibroblast growth factor (FGF)-21 is a unique member of the FGF family, with several molecular characteris- Abstracttics that

9、differ from classical FGFs and exhibiting a pharmacologic profile that includes a variety of metabolicresponses in vitro and when tested in vivo in animal models. FGF21 represents a novel and attractive therapeuticagent

10、for type 2 diabetes mellitus, because of its ability to modulate disease phenotype in preclinical settingswithout inducing any apparent adverse effects. Although FGF21 was discovered relatively recently, theunderstanding

11、 of its biology and therapeutic utility is rapidly evolving. A number of key metabolically linkedmolecules and pathways have been suggested to be involved in the mechanism of action of FGF21, depending onthe specific tar

12、get tissue/organ. Further research into these mechanisms should lead to important advances in theunderstanding of FGF21 biology and pave the way for novel therapeutic strategies. The specifics of FGF21activities both in

13、cell culture and in vivo, its potential as a target for diabetes, and insights into the molecularmechanisms of FGF21 metabolic actions will be discussed in this review.1. The Role of Fibroblast Growth Factors (FGFs) in r

14、odents, respectively.[8,9] When tested in mice, FGF19 providesthe Regulation of Metabolic Processes resistance to obesity and insulin desensitization.[10,11] Anothermember of the FGF family, FGF23, is a key player in the

15、 regula- Fibroblast growth factors (FGFs) and their corresponding re- tion of phosphate and calcium metabolism.[12,13] Likewise, the ceptors (FGFRs) have been primarily associated with the process-es of development, tran

16、sformation, and angiogenesis.[1-4] How- overexpression of a dominant-negative form of FGFR1 in pancre-ever, over the last decade, new data have emerged showing that atic β cells leads to diabetes mellitus in mice.[14] FG

17、FR2 appears to FGF/FGFR-mediated pathways may play important roles in defin- be a key molecule in the process of pancreatic development.[15-17] ing and regulating functions of endocrine-relevant tissues and FGFR3 is a cr

18、itical player in bone,[18] whereas FGFR4 has been organs, as well as modulating various metabolic processes. For implicated in cholesterol metabolism and bile-acid synthesis.[19] example, FGF10 and FGF16 play important r

19、oles in adipocyte and The metabolic roles of FGF/FGFR are still not precisely defined pancreatic biology,[5-7] and FGF19 and its mouse ortholog FGF15,regulate cholesterol and bile-acid metabolism in humans and and are cu

20、rrently under intense investigation.FGF21 and Metabolic Diseases 39induces upregulation of PPARγ protein. Although it is currently incidence of hepatocellular carcinomas in FGF21 transgenic miceunclear what particular im

21、pact each of these effects has on glucose at 12 months of age was similar to that in control animals. Thus, iftransport, these data reveal potential synergy in the actions be- FGF21 negatively regulates chemically induce

22、d hepatocarci-tween these two regulators of glucose homeostasis, FGF21 and nogenesis, it is likely to interfere with disease progression at itsPPARγ.[31] early stages.[24]Recently, another line of FGF21 transgenic mice o

23、n a C57BL/6J background has been described.[26] These animals had 50–150 3. FGF21 In Vivo Pharmacology times higher levels of FGF21 mRNA in the liver than controlanimals, and had lowered levels of serum cholesterol, tri-

24、 The in vivo bioactivity of FGF21 has been observed usingglycerides, glucose and insulin (indicative of the improved lipid numerous biomarkers that illustrate the effects of FGF21 actionsand glycemic metabolism), and ame

25、liorated insulin resistance, in a broad range of animal studies covering a variety of diseaseconsistent with previously published data.[20] FGF21 transgenic models.[20,23-26,35]mice were also found to have elevated serum

26、 levels of β-hydroxy- The consequences of enforced expression of human[20] and butyrate, suggesting the induction of ketogenesis, as well as hav- mouse FGF21[23,26] have been evaluated in transgenic mice.[20,24,26]ing ad

27、ipocytes of smaller size, increased lipase expression in white FGF21 transgenic animals appear viable, normal at birth, and adipose tissue and elevated serum levels of free fatty acids, all essentially indistinguishable

28、from their wild-type littermates. No- evocative of the induction of lypolysis.[26] Importantly, as urine ticeably, they do not possess signs of neoplasia, tumors, or any concentrations of adrenaline and noradrenaline wer

29、e reduced in other overt abnormalities throughout their lifespan, as demonstra- FGF21 transgenic animals, FGF21 does not appear to stimulate ted by extensive morphologic and histologic analyses.[20,23] Thus, lipolysis th

30、rough a systemic increase in catecholamines.[26] Sur- prolonged exposure of mice to FGF21 does not lead to carcinogen- prisingly, these FGF21 transgenic mice were also reported to have ic events. Nevertheless, a specific

31、 phenotype of FGF21 transgenic 1–2ºC lower core body temperatures, reduced locomotor activity, mice was revealed upon a variety of challenges. and enhanced torpor during 24-hour fasting compared with their C57Bl/6 m

32、ice overexpressing human FGF21 from the liver control littermates.[26] Although intriguing, the latter observations (circulating levels of 70–150 ng/mL) were evaluated for changes have not been reported by others[20,24]

33、and, therefore, need to be in metabolic parameters.[20] When fed a high fat, high carbohy- explored further. drate (HFHC) diet for 15 weeks, FGF21 transgenic mice wereAdenovirus-mediated knockdown of FGF21 with short hai

34、rpin resistant to weight gain and fat accumulation, despite an increasedRNA (shFGF21) in mice led to a substantial decrease in circulat- caloric intake. Consistent with low adiposity, the levels of leptining FGF21 levels

35、 and resulted in serious metabolic abnormalities, were noticeably reduced, as well as those of glucagon. Important-such as fatty liver, severe hypertriglyceridemia (predominantly as ly, these effects were not associated

36、only with the HFHC diet, asa result of the increase in chylomicron/very low-density lipo- they were also observed in aged FGF21 transgenic mice on aprotein fraction), a significant elevation in serum free fatty acids nor

37、mal chow diet. At 9 months of age, they weighed significantlyand total cholesterol, and a reduction in serum ketones.[23] Impor- less, had lower fasting glucose levels, less total and liver fat, moretantly, these changes

38、 were apparent only in animals fed a high-fat brown adipocytes, and showed improved glucose clearance anddiet and not on a normal chow diet. This correlates with a dramatic insulin sensitivity compared with control anima

39、ls.[20]elevation in the endogenous expression of FGF21 in animals on a Analysis of FVB mice with liver-specific overexpression of ketogenic diet, and provides further evidence that the outcomes of mouse FGF21 confirmed t

40、he absence of neoplasias or tumors.[24]shFGF21 experiments are indeed a result of a direct attenuation of Moreover, when compared with control animals, no change was endogenous FGF21 expression/function.[23] observed in

41、the incorporation of bromodeoxyuridine (BrdU) intothe livers of FGF21 transgenic mice after partial hepatectomy or Systemic administration of FGF21 in rodents via subcutaneousCCl4 insult, suggesting that FGF21 is unlikel

42、y to play a role in a injections or through constant infusion leads to a variety of meta-compensatory liver restoration process. Unexpectedly, forced ex- bolic consequences. FGF21 effectively lowers fed and fastedpressio

43、n of FGF21 markedly reduces tumor incidence, measured plasma glucose levels, stimulates glucose disposal, and increasesby the frequency of diethylnitrosamine-induced adenomas and the insulin sensitivity in oral glucose t

44、olerance tests.[20] Importantly,timing of their first appearance.[24] However, although FGF21 the FGF21 glucose-lowering effects are long lasting, as theyappears to delay the process of tumor initiation in the liver, the