The incidence of type 2 diabetes mellitus (T2DM) has been increasing annually, which is a serious threat to human health. Fibroblast growth factor 21 (FGF21) is one of the most popular targets for the treatment of diabetes because it effectively improves glycolipid metabolism. In our experiment, human FGF21 (hFGF21) was injected and stably expressed in the liver tissues of a rat T2DM model with lentivirus system. Based on clinical and histopathological examinations, islet cells were protected and liver tissue lesions were repaired for >4 months. Glucose metabolism and histopathology were controlled perfectly when hFGF21 was stably expressed in partial liver of T2DM rats. The results showed that the liver tissue cell apoptosis was reduced, the lipid droplet content was decreased, the oxidative stress indexes were improved, the glycogen content was increased, and the islet cells were increased too. Besides, insulin sensitivity and glycogen synthesis-related genes expression were increased, but cell apoptosis-related genes caspase3 and NFκB expression were decreased. The effectiveness of results suggested that injecting hFGF21 to rats liver could effectively treat T2DM.
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References
1.
KalraS, SabooB, SahayR, et al.The rule of two-thirds in diabetes epidemiology. Indian J Endocrinol Metab, 2017; 21:242–244.
2.
VieiraE, SalehiA, GylfeE. Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia, 2007; 50:370–379.
3.
SalehiA, VieiraE, GylfeE. Paradoxical stimulation of glucagon secretion by high glucose concentrations. Diabetes, 2006; 55:2318–2323.
4.
ChengX, KimSY, OkamotoH, et al.Glucagon contributes to liver zonation. Proc Natl Acad Sci U S A, 2018; 115:E4111–E4119.
DaviesM, ChatterjeeS, KhuntiK. The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies. Clin Pharmacol, 2016; 8:61–81.
7.
Di LulloL, ManganoM, RoncoC, et al.The treatment of type 2 diabetes mellitus in patients with chronic kidney disease: what to expect from new oral hypoglycemic agents. Diabetes Metab Syndr, 2017; 11Suppl 1:S295–S305.
8.
MazzottiA, CalettiMT, MarchignoliF, et al.Which treatment for type 2 diabetes associated with non-alcoholic fatty liver disease?. Dig Liver Dis, 2017; 49:235–240.
9.
NishimuraT, NakatakeY, KonishiM, et al.Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta, 2000; 1492:203–206.
10.
EricksonA, MoreauR.The regulation of FGF21 gene expression by metabolic factors and nutrients. Horm Mol Biol Clin Investig, 2016; 30. DOI: 10.1515/hmbci-2016-0016.
11.
YuY, HeJ, LiS, et al.Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-kappaB signaling pathway. Int Immunopharmacol, 2016; 38:144–152.
12.
HeJL, ZhaoM, XiaJJ, et al.FGF21 ameliorates the neurocontrol of blood pressure in the high fructose-drinking rats. Sci Rep, 2016; 6:29582.
13.
SA-NguanmooP, TanajakP, KerdphooS, et al.FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats. Horm Behav, 2016; 85:86–95.
14.
ZirosP, ZagoritiZ, LagoumintzisG, et al.Hepatic Fgf21 expression is repressed after simvastatin treatment in mice. PLoS One, 2016; 11:e162024.
15.
RusuCC, RacasanS, KacsoIM, et al.The metabolic hormone FGF21 is associated with endothelial dysfunction in hemodialysis patients. Int Urol Nephrol, 2017; 49:517–523.
16.
OstM, ColemanV, VoigtA, et al.Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action. Mol Metab, 2016; 5:79–90.
17.
YeX, QiJ, YuD, et al.Pharmacological efficacy of FGF21 analogue, liraglutide and insulin glargine in treatment of type 2 diabetes. J Diabetes Complications, 2017; 31:726–734.
18.
ParkJG, XuX, ChoS, et al.CREBH-FGF21 axis improves hepatic steatosis by suppressing adipose tissue lipolysis. Sci Rep, 2016; 6:27938.
19.
JaegerD, SchoiswohlG, HoferP, et al.Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids. J Hepatol, 2015; 63:437–445.
20.
LiangQ, ZhongL, ZhangJ, et al.FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes, 2014; 63:4064–4075.
21.
FisherFM, Maratos-FlierE. Understanding the physiology of FGF21. Annu Rev Physiol, 2016; 78:223–241.
SpontonCH, KajimuraS. AAV-mediated gene therapy as a strategy to fight obesity and metabolic diseases. EMBO Mol Med, 2018; 10:pii: e9431.
26.
JimenezV, JambrinaC, CasanaE, et al.FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Mol Med, 2018; 10:pii: e8791.
27.
WangY, BergelsonS, FeschenkoM. Determination of lentiviral infectious titer by a novel droplet digital PCR method. Hum Gene Ther Methods, 2018; 29:96–103.
28.
LuSY, QiSD, ZhaoY, et al.Type 2 diabetes mellitus non-genetic Rhesus monkey model induced by high fat and high sucrose diet. Exp Clin Endocrinol Diabetes, 2015; 123:19–26.
29.
SinghS, KhanI, KhimS, et al.Safe and effective gene therapy for murine Wiskott-Aldrich syndrome using an insulated lentiviral vector. Mol Ther Methods Clin Dev, 2017; 4:1–16.
30.
QianW, WangY, LiRF, et al.Prolonged integration site selection of a lentiviral vector in the genome of human keratinocytes. Med Sci Monit, 2017; 23:1116–1122.
31.
TanajakP, SA-NguanmooP, WangX, et al.Fibroblast growth factor 21 (FGF21) therapy attenuates left ventricular dysfunction and metabolic disturbance by improving FGF21 sensitivity, cardiac mitochondrial redox homoeostasis and structural changes in pre-diabetic rats. Acta Physiol (Oxf), 2016; 217:287–299.
32.
LynchL, HoganAE, DuquetteD, et al.iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 Therapy. Cell Metab, 2016; 24:510–519.
33.
DongJQ, RossulekM, SomayajiVR, et al.Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol, 2015; 80:1051–1063.
34.
XuJ, StanislausS, ChinookoswongN, et al.Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects. Am J Physiol Endocrinol Metab, 2009; 297:E1105–E1114.
35.
ShaoM, YuL, ZhangF, et al.Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model. Am J Physiol Endocrinol Metab, 2015; 309:E45–E54.
36.
SchlessingerK, LiW, TanY, et al.Gene expression in WAT from healthy humans and monkeys correlates with FGF21-induced browning of WAT in mice. Obesity (Silver Spring), 2015; 23:1818–1829.
37.
SockoloskyJT, KivimaeS, SzokaFC. Fusion of a short peptide that binds immunoglobulin G to a recombinant protein substantially increases its plasma half-life in mice. PLoS One, 2014; 9:e102566.
38.
KubickyRA, WuS, KharitonenkovA, et al.Role of fibroblast growth factor 21 (FGF21) in undernutrition-related attenuation of growth in mice. Endocrinology, 2012; 153:2287–2295.
39.
ReinehrT, WoelfleJ, WunschR, et al.Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. J Clin Endocrinol Metab, 2012; 97:2143–2150.
40.
Lenart-LipinskaM, Matyjaszek-MatuszekB, GernandW, et al.Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up. Diabetes Res Clin Pract, 2013; 101:194–200.
41.
LiuJ, XuY, HuY, et al.The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism, 2015; 64:380–390.
42.
Cante-BarrettK, MendesRD, SmitsWK, et al.Lentiviral gene transfer into human and murine hematopoietic stem cells: size matters. BMC Res Notes, 2016; 9:312.
43.
YuH, FischerG, JiaG, et al.Lentiviral gene transfer into the dorsal root ganglion of adult rats. Mol Pain, 2011; 7:63.
44.
BanerjeeD, ShimaokaM. Lentiviral gene transfer method to study integrin function in T lymphocytes. Methods Mol Biol, 2012; 757:47–54.
45.
BadilloAT, ChungS, ZhangL, et al.Lentiviral gene transfer of SDF-1alpha to wounds improves diabetic wound healing. J Surg Res, 2007; 143:35–42.
46.
BursillCA, McneillE, WangL, et al.Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition. Gene Ther, 2009; 16:93–102.
47.
BemelmansAP, KosticC, CachafeiroM, et al.Lentiviral gene transfer-mediated cone vision restoration in RPE65 knockout mice. Adv Exp Med Biol, 2008; 613:89–95.
48.
ClarJ, MutelE, GriB, et al.Hepatic lentiviral gene transfer prevents the long-term onset of hepatic tumours of glycogen storage disease type 1a in mice. Hum Mol Genet, 2015; 24:2287–2296.
49.
ZhangE, MohammedAI, MohammedS, et al.Preserving insulin secretion in diabetes by inhibiting VDAC1 overexpression and surface translocation in beta cells. Cell Metab, 2019; 29:64–77.
50.
WangH, XiaoY, FuL, et al.High-level expression and purification of soluble recombinant FGF21 protein by SUMO fusion in Escherichia coli. BMC Biotechnol, 2010; 10:14.
51.
YaoWB, RenGP, HanY, et al.[Expression and pharmacological evaluation of fusion protein FGF21-L-Fc]. Yao Xue Xue Bao, 2011; 46:787–792.
52.
TanakaH, ShimizuN, YoshikawaN. Role of skeletal muscle glucocorticoid receptor in systemic energy homeostasis. Exp Cell Res, 2017; 360:24–26.
53.
HuangZ, XuA, CheungBM. The potential role of fibroblast growth factor 21 in lipid metabolism and hypertension. Curr Hypertens Rep, 2017; 19:28.
54.
StanislausS, HechtR, YieJ, et al.A novel Fc FGF21 with improved resistance to proteolysis, increased affinity towards beta-Klotho and enhanced efficacy in mice and cynomolgus monkeys. Endocrinology, 2017; 158:1314–1327.
55.
KimGY, KwonJH, ChoJH, et al.Downregulation of pathways implicated in liver inflammation and tumorigenesis of glycogen storage disease type Ia mice receiving gene therapy. Hum Mol Genet, 2017; 26:1890–1899.
56.
WeiW, DutchakPA, WangX, et al.Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci U S A, 2012; 109:3143–3148.
57.
SinghalG, DourisN, FishAJ, et al.Fibroblast growth factor 21 has no direct role in regulating fertility in female mice. Mol Metab, 2016; 5:690–698.
58.
OwenBM, BookoutAL, DingX, et al.FGF21 contributes to neuroendocrine control of female reproduction. Nat Med, 2013; 19:1153–1156.
59.
NelsonBT, DingX, Boney-MontoyaJ, et al.Metabolic hormone FGF21 is induced in ground squirrels during hibernation but its overexpression is not sufficient to cause torpor. PLoS One, 2013; 8:e53574.
60.
ZhangG, WangQ, ZhouQ, et al.Protective effect of tempol on acute kidney injury through PI3K/Akt/Nrf2 signaling pathway. Kidney Blood Press Res, 2016; 41:129–138.
61.
TongqiangL, ShaopengL, XiaofangY, et al.Salvianolic acid B prevents iodinated contrast media-induced acute renal injury in rats via the PI3K/Akt/Nrf2 pathway. Oxid Med Cell Longev, 2016; 2016:7079487.
62.
ZhangY, WeiZ, LiuW, et al.Melatonin protects against arsenic trioxide-induced liver injury by the upregulation of Nrf2 expression through the activation of PI3K/AKT pathway. Oncotarget, 2017; 8:3773–3780.
63.
WangZ, XiongL, WangG, et al.Insulin-like growth factor-1 protects SH-SY5Y cells against beta-amyloid-induced apoptosis via the PI3K/Akt-Nrf2 pathway. Exp Gerontol, 2017; 87:23–32.
64.
MoyersJS, ShiyanovaTL, MehrbodF, et al.Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. J Cell Physiol, 2007; 210:1–6.
65.
PlanavilaA, Redondo-AnguloI, RibasF, et al.Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res, 2015; 106:19–31.
66.
Gomez-SamanoMA, Grajales-GomezM, Zuarth-VazquezJM, et al.Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biol, 2017; 11:335–341.
67.
PlanavilaA, RedondoI, HondaresE, et al.Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun, 2013; 4:2019.
68.
LiuY, PalanivelR, RaiE, et al.Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes, 2015; 64:36–48.
LiuY, WangC, WangY, et al.Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells. Toxicol Appl Pharmacol, 2012; 264:212–221.
71.
YuY, LiS, LiuY, et al.Fibroblast growth factor 21 (FGF21) ameliorates collagen-induced arthritis through modulating oxidative stress and suppressing nuclear factor-kappa B pathway. Int Immunopharmacol, 2015; 25:74–82.
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