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1、Full Terms&Conditions of access and use can be found athttps:/ Review of Gastroenterology&HepatologyISSN:(Print)(Online)Journal homepage:https:/ key player in the pathogenesis ofnon-alcoholic fatty liver disease?Liang-Jie Tang,Rafael S.Rios,Huai Zhang,Christopher D.Byrne,GiovanniTargher&Ming-Hua Zhe

2、ngTo cite this article:Liang-Jie Tang,Rafael S.Rios,Huai Zhang,Christopher D.Byrne,GiovanniTargher&Ming-Hua Zheng(2021)Telomerase:a key player in the pathogenesis of non-alcoholicfatty liver disease?,Expert Review of Gastroenterology&Hepatology,15:7,811-819,DOI:10.1080/17474124.2021.1903318To link t

3、o this article:https:/doi.org/10.1080/17474124.2021.1903318Published online:19 Mar 2021.Submit your article to this journal Article views:91View related articles View Crossmark dataREVIEWTelomerase:a key player in the pathogenesis of non-alcoholic fatty liver disease?Liang-Jie Tanga,Rafael S.Riosa,H

4、uai Zhanga,Christopher D.Byrneb,Giovanni Targherc and Ming-Hua Zhenga,d,eaNAFLD Research Center,Department of Hepatology,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China;bSouthampton National Institute for Health Research Biomedical Research Centre,University Hospital Southa

5、mpton,Southampton General Hospital,Southampton,UK;cSection of Endocrinology,Diabetes and Metabolism,Department of Medicine,University and Azienda Ospedaliera Universitaria Integrata of Verona,Verona,Italy;dInstitute of Hepatology,Wenzhou Medical University,Wenzhou,China;eKey Laboratory of Diagnosis

6、and Treatment for the Development of Chronic Liver Disease in Zhejiang Province,Wenzhou,ChinaABSTRACTIntroduction:Telomerase is a basic nuclear protein reverse transcriptase,which plays a key role in maintaining telomere stability,genome integrity,long-term cell activity,and potential continued prol

7、iferation.Area covered:This narrative review discusses key research advances involving telomerase in the development and progression of nonalcoholic fatty liver disease(NAFLD).The review evaluates 9a)whether the assessment of telomerase can be used as a noninvasive diagnostic tool;and(b)whether modi

8、fication of telomerase function might be a useful potential therapeutic target for treatment of NAFLD.Furthermore,the relationship between telomerase and other chronic metabolic diseases is evaluated.Expert opinion:Several experimental and preclinical studies have suggested that telomerase plays an

9、important role in the development of NAFLD.However,further mechanistic studies are needed to prove a causal relationship and to better elucidate whether the measurement of telomerase has utility as a diagnostic tool or whether pharmacological manipulation of telomerase has therapeutic potential in N

10、AFLD treatment.ARTICLE HISTORYReceived 17 November 2020 Accepted 10 March 2021 KEYWORDSTelomerase;nonalcoholic fatty liver disease;liver fibrosis;lipid metabolism;hepatocellular carcinoma;metabolic disorders;therapeutic targets1.IntroductionNonalcoholic fatty liver disease(NAFLD)is now one of the mo

11、st common liver diseases due to the increasing prevalence of metabolic diseases,such as obesity and type 2 diabetes 1.Because more than a quarter of people suffer from NAFLD,this liver disease now represents an increasing global health problem and economic burden 2,3.In addition to multiple environm

12、ental risk factors,there is also a strong association between NAFLD and genetic factors 4.Indeed,somatic genetic mutations occurring in multiple loci may affect hepatic lipid metabolism,leading to the development of NAFLD and accelerating its progression to nonalcoholic steatohepatitis(NASH)and cirr

13、hosis 5.Among these genetic factors,telomere and telomerase play important roles in the development of NAFLD 6.In particular,telomerase dysfunction may lead to telomere shortening that affects the normal function of liver cells,lipid metabolism,and hepatic fibrogenesis and may pro-mote progression o

14、f NAFLD to NASH 7,cirrhosis and hepato-cellular carcinoma(HCC)8.This narrative review discusses key research advances regarding the link between telomerase and NAFLD development and progression.Whether telomerase could be used as a noninvasive diagnostic tool and potential therapeutic target for pat

15、ients with NAFLD is also discussed,together with the relationship between telomerase and other related chronic metabolic diseases.2.Telomeres and telomeraseIn the human genome,telomeres are a small DNA-protein complex located at the end of the chromosome.The length of telomeres DNA varies from 5 kb

16、to 15 kb 9.Telomeres are composed of hexanucleotide repeat segments(TTAGGG)10(Figure 1),which improve the structural stability of chromo-somes and protect the end portion of chromosomes from end-to-end fusion,rearrangement,and translocation during the processes of cell proliferation.However,telomere

17、s lose about 50100 base pairs in each mitotic cycle,since DNA polymerases cannot fully replicate the 3 end of the lagging chain(due to a process called telomere attrition),and there-fore the telomere length gradually shortens during cell pro-liferation 11,12.Human cells can only replicate a certain

18、number of times before they undergo programmed cell death,according to the Hayflick limit concept on cell aging.When the telomere is shortened to the Hayflick limit 13,the cell stops mitosis,activates the DNA apoptosis program,and enters into the cellular aging process.Therefore,telomere length can

19、be used as a life clock to describe the aging of cells 14.Telomerases are ribonuclease complexes,closely related to the telomeres,participating in the mitotic phases of the cells,which are involved in the process of DNA replication,as well as in the synthesis of new DNA sequences.Adding DNA to the C

20、ONTACT Ming-Hua Zheng NAFLD Research Center,Department of Hepatology,The First Affiliated Hospital of Wenzhou Medical University;No.2 Fuxue Lane,Wenzhou 325000,China.EXPERT REVIEW OF GASTROENTEROLOGY&HEPATOLOGY 2021,VOL.15,NO.7,811819https:/doi.org/10.1080/17474124.2021.1903318 2021 Informa UK Limit

21、ed,trading as Taylor&Francis Groupends of chromosomes allows them to stabilize the telomere length and reduce the speed of telomere shortening.Telomerase consists of two main parts:the telomerase RNA component(hTERC)and the telomerase reverse transcriptase(including its RNA template)(hTERT)15.hTERC

22、combines with the Dyskerin complex,which is composed of four nucleo-lar proteins:Dyskerin(DKC1)and members 1,2,and 3 of nucleolar protein family A(i.e.NOLA1,NOLA2,and NOLA3).The function of the Dyskerin complex is to stabilize and pro-tect the structure and function of hTERC 1618.The human Shelterin

23、 complex consists of six core proteins:telomeric repeat-binding factor 1 and 2(TRF1,TRF2),TRF1-interacting protein 2(TIN2),TRF2-interacting protein 1(RAP1),protection of telomeres 1(POT1),and telomere-binding pro-tein POT1-interacting protein 1(TPP1)19.TRF1 and TRF2 bind to telomere double-stranded

24、DNA.TPP1 combines with POT1,to recruit POT1 to the telomere region.POT1 can,specifically,recognize telomere single-stranded DNA.RAP1 binds with TRF2,to access the telomerase.Finally,TIN2 acts as a bridge,connecting POT1-TPP1 to TRF1 and TRF2,thus binding the whole Shelterin complex together.The Shel

25、terin complex,by binding to telomeres specifically,helps to cap telomeres.Additionally,as shown in Figure 1,the Shelterin complex also plays an important role in regulating telomere length,in maintaining telomere structure,and in adding func-tional integrity 20.3.Telomerase in NAFLDPrevious studies

26、have shown that the dysfunction and somatic genetic mutations of both hTERT and hTERC are relevant to several chronic liver diseases 21.Dysfunction or gene muta-tions of both hTERT and hTERC affect telomere shortening that will consequentially lead to a decline of hepatocyte regenera-tive ability,an

27、d metabolic dysfunction 22,making the liver prone to fatty degeneration,inflammation and fibrosis.Furthermore,after liver damage occurs,with increasing levels of fibrosis,the liver is increasingly susceptible to the develop-ment of HCC.Therefore,telomere length may be a reliable genetic marker to mo

28、nitor the progress of pathologic liver conditions,especially,the development and progression of chronic liver diseases 2325.3.1.Telomerase in fatty liver degenerationRecent findings suggest that impaired lipid handling by hepa-tocytes plays a key role in the pathogenesis of NAFLD by triggering infla

29、mmation,fibrogenesis,and carcinogenesis 26.NAFLD can be observed in individuals with telomerase dysfunction,suggesting that telomerase may be involved in hepatic lipid metabolism.It is currently uncertain whether telomerase function may be regulated to improve the liver disease,or whether telomerase

30、 function could be used to predict the progression and evaluate the prognosis of NAFLD.Additionally,telomerase is closely related to cellular Article highlightsThe specific role of telomerase function in hepatocytes is discussed.Fatty degeneration,cellular inflammation,oxidative stress,mitochon-dria

31、l dysfunction,as well as fibrosis and increased susceptibility to cancer in the liver are considered to be pathological changes poten-tially induced by telomerase dysfunction.A novel therapeutic strategy to regulate telomere length by improv-ing telomerase function in NAFLD is also considered.Figure

32、 1.Location and composition of telomeres and the structure of telomerase.In the human genome,telomeres are a small DNA-protein complex located at the end of chromosome and composed of hexanucleotide repeat segments(TTAGGG)in 3 end of the lagging chain.Telomerase binds to telomere and is mainly compo

33、sed of hTERC and hTERT.Among them,Dyskerin complex adheres to hTERC to stabilize and protect it;Shelterin complex interacts with telomere to regulate telomere length.812L.-J.TANG ET AL.aging,and it is plausible that hepatocytes are more suscepti-ble to steatosis with aging 27.Studies have shown that

34、 there are patients with severe hepatic steatosis who have impaired mitochondrial telomerase function(since hTERT protects mitochondrial DNA from damage 28),regardless of the presence of NASH 29,30.It is plausible that increased uptake of free fatty acids(FFA)into hepatocytes among patients with NAF

35、LD increases intracellular amounts of reactive oxygen species(ROS),due to the increase in oxidative stress in vivo(oxidation of base G in the telomere sequence)31.This effect would delay telomerase activation and decrease telomerase activ-ity,resulting in the breaking and shortening of the telomere,

36、under non-replicative conditions 32.Thus,we surmise that in patients with NAFLD,the oxidative damage caused by high levels of ROS in hepatocytes may be the main cause of telomere short-ening and that the degree of hepatic steatosis,rather than that of fibrosis,might play a leading role in telomere s

37、hortening 33(see Figure 2).In addition,the Shelterin complex binding to telomerase plays a role in protecting the length of the telomere at the end of the chromosome 34.RAP1 is one of the components involved in the process of lipid metabolism 35.It has been experimentally demonstrated that if RAP1 i

38、s absent(resulting in telomerase dysfunction),fatty liver degeneration,impaired glucose tolerance,and increased abdominal fat accumulation may occur in mice 36.Furthermore,hTERT mutation may induce telomerase dys-function,leading to a series of familial liver diseases.These familial liver diseases a

39、re usually characterized by hepatic steatosis and iron overload of hepatocytes,which may be caused by erythropoiesis-related disorders 37.In summary,the dysfunction of telomeres and telomerase may lead to fat accumulation in hepatocytes and the occurrence of NAFLD.3.2.Telomerase in liver fibrosisSom

40、atic genetic mutations of the telomerase gene(especially hTERT)may accelerate the process of telomere shortening and affect the regenerative ability of hepatocytes,thereby promot-ing hepatic fibrogenesis 38,39.The causal effect of this gene mutation has been confirmed in mouse models with telomer-as

41、e deficiency.After three generations,the telomeres of these mice became shorter,and the development of fibrosis accel-erated after liver injury 40,41.Conversely,over-expression of hTERT activity improved the stability of telomerase and length of telomere,delayed the progress of liver fibrosis in the

42、se mice.In chronic liver diseases(such as cirrhosis),tissue regenera-tion is increased,cell division is expedited,and telomere short-ening is accelerated.When telomeres become extremely short,cell apoptosis occurs,leading to further reduction of the num-ber of hepatocytes 42.Therefore,telomere short

43、ening is also considered a marker of cirrhosis 43.In cirrhotic patients,telomere shortening is associated with the expression of some cellular senescence markers,such as-galactosidase,p16,p21,and p53 proteins 44,45.P53 protein is the key regulatory point within the cell apoptosis signal pathway.P53

44、phosphorylation induces p21 expression and p21 binds to cyclin-dependent kinase(Cdk)complex.Binding to the cyclin-dependent kinase(Cdk)complex inhibits its activity,resulting in the accumulation of nuclear protein pRB in cells,inhibiting the transcription of E2F target gene required for cell cycle p

45、rogression,and causing G1 phase arrest of cell division.Nuclear protein pRB can also be activated by p16 protein,which is also an inhibitor of Cdk activity,usually found in aging cells 45.It has been reported that telomere shortening in per-ipheral blood leukocytes is independently associated with a

46、n increased risk of advanced liver fibrosis.In fact,Kim et al.reported that the association between telomere length in blood leukocytes and advanced liver fibrosis remained statistically significant even after adjusting for obesity and other risk factors,suggesting that the telo-mere length of these

47、 cells may play a role in mediating the link between NAFLD and advanced fibrosis,especially in the elderly 46.Figure 2.Telomerase is related to fat metabolism in vivo.The increase in free fatty acid(FFA)uptake in cells leads to the increased production of reactive oxygen species(ROS).Oxidative stres

48、s causes the oxidation of base G in telomere sequence,resulting in delayed telomerase activation and decreased telomerase activity,resulting in telomere breakage and shortening under non-replicative conditions;Rap1 is involved in the lipid metabolism process in vivo.If the telomerase dysfunction occ

49、urs due to the lack of Rap1,it will lead to hepatic steatosis,impaired glucose tolerance and increased abdominal fat accumulation in mice;the disorder of red blood cell formation will lead to steatosis and iron overload in liver cells,which will eventually lead to lipid metabolism disorder and incre

50、ase the susceptibility to NAFLD.EXPERT REVIEW OF GASTROENTEROLOGY&HEPATOLOGY8133.3.Telomerase in NAFLD-related HCCIn immortalized cells(such as cancer cells,stem cells,and germ cells),telomerase activity increases,delaying telomere shortening,and even extending telomere length 25.Some studies have f