脂肪肝与糖代谢紊乱课件

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1、非酒精性脂肪肝与非酒精性脂肪肝与2 2型糖尿病型糖尿病1人类对脂肪肝与糖尿病的认识人类对脂肪肝与糖尿病的认识1906年：年：“Hepatogenous diabetes”肝源性糖尿病肝源性糖尿病 肝硬化患者中多发糖尿病肝硬化患者中多发糖尿病1980年：年：Ludwig et al.首次提出首次提出“非酒精性脂肪性肝炎非酒精性脂肪性肝炎NASH”的命名的命名 20例、几乎不饮酒、其中例、几乎不饮酒、其中19例肥胖例肥胖/超重、多伴有糖尿病超重、多伴有糖尿病 肝活检病理：肝脂肪变性、小叶炎症、灶性坏死、炎症细肝活检病理：肝脂肪变性、小叶炎症、灶性坏死、炎症细 胞浸润、胞浸润、Mallory小体、纤

2、维化小体、纤维化、甚至肝硬化，其形态学改变与甚至肝硬化，其形态学改变与 酒精脂肪肝非常相似酒精脂肪肝非常相似1999年：年：Matteoni 等，根据肝活检和长期观察的结局性研究证据，发现等，根据肝活检和长期观察的结局性研究证据，发现 非酒精性脂肪肝严重程度不同，是一组从单纯性脂肪肝到脂肪非酒精性脂肪肝严重程度不同，是一组从单纯性脂肪肝到脂肪性性 肝炎以致纤维化的疾病谱，首次提出肝炎以致纤维化的疾病谱，首次提出NAFLD的定义的定义Ludwig J,et al.Mayo Clin Proc 1980;55:434 438 Paola Loria，et al.Hepatology Researc

3、h 2013;43:5164 Perseghin G,et al.Hepatology 2000;31:694703.Alina Pascaleet al.J Gastrointestin Liver Dis 2010 Vol.19 No 4,415-423 Matteoni CA,et al.Gastroenterology 1999;116:14131419 2非酒精性脂肪性肝病是一个疾病谱非酒精性脂肪性肝病是一个疾病谱Cohen JC,et al.Science 2011,332:1519-1523.3ALT as a Predictor of Type 2 Diabetes A pro

4、spective study in Pima Indians605040302010005101520years of follow-up incidence type 2 diabetesUpper tertile of ALT(59 mU/l)Lower tertile of ALT(21 mU/l)Vozarova B,Diabetes 51:18891895,20024肝酶升高预测糖尿病前期和肝酶升高预测糖尿病前期和2型糖尿病的发生型糖尿病的发生The Bogalusa Heart Study（follow up over 16 years）Diabetes Care.2011 Dec

5、;34(12):2603-7and al coholdri nki ng(yes/no)observedsi nce basel i ne as l ongi t udi nalcat egori calvari abl esand BM I,M AP,H DL chol est erol,LDL chol est erol,t ri gl yceri des,and H O M A-IR asl ongi t udi nalcont i nuousvari abl es,aswel lasALT and GGT(m odel1 and 2,re-spect i vel y),adj ust

6、edf orst udyyear,age,agesquared,race,sex,and sex byracei nt erac-ti on,as appl i cabl e.O dds rati os are ex-pressed per1-SD i ncrem enti n BM I,M AP,H DL chol est erol,LDL chol est erol,t ri gl y-ceri des,H O M A-IR,ALT,and GGT.N on-si gni f i cantt erm s(P.0.05)wererem ovedf rom t hem odelbybackwa

7、rd st epwi sepro-cedure.To eval uat e t he di scri m i nat ory ca-pabi l i t yoft hem odel susi ngt heareaundert herecei veroperat i ng charact eri st i c(RO C)curve(C st at i st i c),t hem ul t i vari at eC st at i s-t i c l ogi st i c regressi onswere perf orm ed ont heassoci at i onoft hebasel i

8、nel i verf unct i onenzym esand gl ucosehom eost asi svari abl es(gl ucose,i nsul i n,and H O M A-IR)wi t h pre-di abet esordi abet esst at usatt hef ol l ow-upi n adul t hood adj ust ed f or age,race,sex,sm oki ng,dri nki ng,BM I,M AP,H DL cho-l est erol,LDL chol est erol,and t ri gl yceri des.RO C

9、s(C val ues)weret est ed f orequal i t ybydi abet esst at usand bypai rwi secom pari sonofeach m odelwi t h t herest.R ESU LTS d M ean l evel s of ant hropo-m et ri c,hem odynam i c,m et abol i c,and l i verf unct i on enzym e vari abl es atbasel i ne arepresent ed i n Tabl e1 byf ol l ow-up di abet

10、 esst at us.The predi abet i c group,versus t henorm ogl ycem i c group,di spl ayed si gni f i-cantl y hi gher systol i c bl ood pressure,M AP,LDL chol esterol,gl ucose,i nsul i n,H O M A-IR,and ALT.The di abet i c group,versus the norm ogl ycem i c group,di s-pl ayed hi gherBM I,syst ol i cbl ood p

11、ressure,di ast ol i c bl ood pressure,M AP,LDL cho-l esterol,tri gl yceri des,gl ucose,i nsul i n,H O M A-IR,ALT,and G G T and low erH DL chol est erol.The f ol l ow-up preval ence rat e ofdi-abet es status af t er a 16-year i ntervalbyquart i l es of basel i ne ALT and GGT i sshown i n Fi g.1.Si gn

12、i f i cantadverset rendsofALT and GGT werenot ed f orbot h pre-di abet i c(P,0.01)and di abet i c(P,0.05)groups.Tabl e 2 show sthe resul t sofa m ul t i-vari abl e adj usted l ongi tudi nall ogi sti cre-gressi on m odelt hati ncl uded BM I,M AP,H DL chol esterol,LDL chol esterol,tri gl y-ceri des,an

13、d H O M A-IR al ong w i th ALT(m odel1)and GGT(m odel2)asam ul t i pl erepeat ed-m easurem entst andardi zed vari-abl e(z scores)and sm oki ng(yes/no)andal coholdri nki ng(yes/no)asal ongi t udi nalrepeat ed-m easurem entcat egori calvari abl eobserved si ncebasel i ne.Af t eradj ust i ngf orst udy

14、year,age,race,sex,and race by sexi nt eracti on(as appl i cabl e),expressed per1-SD i ncrease,H O M A-IR showed asi gni f-i cantoddsrat i o of1.70(P,0.0001)f ordevel opi ng f ol l ow-up predi abetesaf t eranaverage of16 yearsoff ol l ow-up.N ei t herALT norGGT show ed si gni f i cantoddsra-t i osi n

15、 t hi sregard.W i t h respectt o devel-opi ng f ol l ow-up di abetes,t he oddsrat i osper1-SD i ncreasewere1.16(P=0.05)f orALT and 1.20(P,0.01)f orGGT.BM I,tri gl yceri des,and H O M A-IR di spl ayedodds rat i os of1.77,1.26,and 1.57,re-spect i vel y(P,0.05);BM Iand t ri gl ycer-i desshow ed oddsrat

16、 i osof2.23 and 1.36,respect i vel y,i n m odel2(P,0.001).N osi gni f i cantracedi f f erencei n t hepredi cti veval ue ofl i ver f unct i on enzym es was ob-served f or ei t her predi abetes or di abetes(dat a notshow n).In t erm s ofdi scri m i nati ve val ues ofdi f f erentbasel i ne l i verf unc

17、t i on enzym esand gl ucose hom eostasi s vari abl es(gl u-cose,i nsul i n,and H O M A-IR)(Tabl e 3),t hepredi cti vem odel sproduced C val uesFigure 1d Prevalence off ol low-up di abetes status by quarti les ofbasel ine ALT and G G Tl evel si n theBogal usa H eartStudy.ALT and G G T val uesby quart

18、i l esw ere,13.0 U I/L and,10U I/L f orquarti l e1;f rom 13to18U I/L and10to14U I/L f orquarti l e2;from 19to28U I/Land 15 to 22 U I/L f orquartil e 3;and f rom 29 to 126 U I/L and 23 to 476 U I/L f orquarti le4,respecti vel y.care.di abetesj ournal s.orgDIABETESCARE,VO LUM E34,DECEM BER20112605N gu

19、yen and Associ atesand al coholdri nki ng(yes/no)observedsi nce basel i ne as l ongi t udi nalcat egori calvari abl esand BM I,M AP,H DL chol est erol,LDL chol est erol,t ri gl yceri des,and H O M A-IR asl ongi t udi nalcont i nuousvari abl es,aswel lasALT and GGT(m odel1 and 2,re-spect i vel y),adj

20、 ust edf orst udyyear,age,agesquared,race,sex,and sex by racei nt erac-ti on,as appl i cabl e.O dds rati os are ex-pressed per1-SD i ncrem enti n BM I,M AP,H DL chol est erol,LDL chol est erol,t ri gl y-ceri des,H O M A-I R,ALT,and GGT.N on-si gni f i cantt erm s(P.0.05)wererem ovedf rom t hem odelb

21、ybackward st epwi sepro-cedure.To eval uat e t hedi scri m i nat ory ca-pabi l i t yoft hem odel susi ngt heareaundert herecei veroperat i ngcharact eri st i c(RO C)curve(C st at i st i c),t hem ul t i vari at eC st at i s-t i c l ogi st i c regressi onswere perf orm ed ont heassoci at i onoft hebas

22、el i nel i verf unct i onenzym esandgl ucosehom eost asi svari abl es(gl ucose,i nsul i n,and H O M A-I R)wi t h pre-di abet esordi abet esst at usatt hef ol l ow-upi n adul t hood adj ust ed f or age,race,sex,sm oki ng,dri nki ng,BM I,M AP,H DL cho-l est erol,LDL chol est erol,and t ri gl yceri des

23、.RO Cs(C val ues)weret est ed f orequal i t ybydi abet esst at usand bypai rwi secom pari sonofeach m odelwi t h t herest.R ESU LTS d M ean l evel s of ant hropo-m et ri c,hem odynam i c,m et abol i c,and l i verf unct i on enzym e vari abl es atbasel i ne arepresent ed i n Tabl e1 byf ol l ow-up di

24、 abet esst at us.The predi abet i c group,versus t henorm ogl ycem i c group,di spl ayed si gni f i-cantl y hi gher systol i c bl ood pressure,M AP,LDL chol esterol,gl ucose,i nsul i n,H O M A-I R,and ALT.The di abet i c group,versus the norm ogl ycem i c group,di s-pl ayed hi gherBM I,syst ol i cbl

25、 ood pressure,di ast ol i c bl ood pressure,M AP,LDL cho-l esterol,tri gl yceri des,gl ucose,i nsul i n,H O M A-IR,ALT,and G G T and l ow erH DL chol est erol.The f ol l ow-up preval ence rat e ofdi-abet es status af t er a 16-year i ntervalbyquart i l es of basel i ne ALT and GGT i sshown i n Fi g.

26、1.Si gni f i cantadverset rendsofALT and GGT werenot ed f orbot h pre-di abet i c(P,0.01)and di abet i c(P,0.05)groups.Tabl e 2 show sthe resul t sofa m ul t i-vari abl e adj usted l ongi tudi nall ogi sti cre-gressi on m odelt hati ncl uded BM I,M AP,H DL chol esterol,LDL chol esterol,tri gl y-ceri

27、 des,and H O M A-IR al ong w i th ALT(m odel1)and GGT(m odel2)asam ul t i pl erepeat ed-m easurem entst andardi zed vari-abl e(z scores)and sm oki ng(yes/no)andal coholdri nki ng(yes/no)asal ongi t udi nalrepeat ed-m easurem entcat egori calvari abl eobserved si ncebasel i ne.Af t eradj ust i ngf or

28、st udy year,age,race,sex,and race by sexi nt eracti on(as appl i cabl e),expressed per1-SD i ncrease,H O M A-IR showed asi gni f-i cantoddsrat i o of1.70(P,0.0001)f ordevel opi ng f ol l ow-up predi abetesaf t eranaverage of16 yearsoff ol l ow-up.N ei t herALT norGGT show ed si gni f i cantoddsra-t

29、i osi n t hi sregard.W i t h respectt o devel-opi ng f ol l ow-up di abetes,t he oddsrat i osper1-SD i ncreasewere1.16(P=0.05)f orALT and 1.20(P,0.01)f orGGT.BM I,tri gl yceri des,and H O M A-IR di spl ayedodds rat i os of1.77,1.26,and 1.57,re-spect i vel y(P,0.05);BM Iand t ri gl ycer-i desshow ed

30、oddsrat i osof2.23 and 1.36,respect i vel y,i n m odel2(P,0.001).N osi gni f i cantracedi f f erencei n t hepredi cti veval ue ofl i ver f unct i on enzym es was ob-served f or ei t her predi abetes or di abetes(dat anotshow n).In t erm s ofdi scri m i nati ve val ues ofdi f f erentbasel i ne l i ve

31、rf unct i on enzym esand gl ucose hom eostasi s vari abl es(gl u-cose,i nsul i n,and H O M A-IR)(Tabl e 3),t hepredi cti vem odel sproduced C val uesFi gure 1d Prevalence off ol l ow-up di abetes status by quarti l es ofbasel ine ALT and G G Tl evel si n theBogal usa H eartStudy.ALT and G G T val ue

32、sby quarti l esw ere,13.0 U I/L and,10U I/L f orquarti l e1;from 13 to18U I/L and10to14 U I/L f orquarti l e2;from 19to28U I/Land 15 to 22 U I/L forquartil e 3;and from 29 to 126 U I/L and 23 to 476 U I/L f orquarti le4,respecti vel y.care.di abetesj ournal s.orgDIABETESCARE,VO LUM E34,DECEM BER2011

33、2605N guyen and Associ ates5NAFDL是2型糖尿病发生的预测因素Sung KC,Kim SH,J Clin Endocrinol Metab2011;96:10931097 Farrell GC,J Gastroen terol Hepatol 2011;26:510 516 Ortiz-Lopez C,.,Cusi K Diabetes Care 2012;35:873 878 Kim SW,Diabetes Care 2011;34:727729 Musso G，et al.Ann Med.2011 Dec;43(8):617-49Williams et al.

34、Endocr Rev.2013 Feb;34(1):84-129韩国：韩国：Sung KC:11091例基线糖代谢正常受试者例基线糖代谢正常受试者 随访随访5年，年，NAFLD发生发生T2DM 风险风险 OR 5.05(CI,2.08 12.29)Kim SW:2049例非例非DM受试者，受试者，随访随访4年，年，基线存在基线存在NAFLD和和IFG患者发生患者发生2型糖尿病型糖尿病 风险风险 HR8.95(CI,6.49 12.35)意大利：意大利：Musso G：荟萃分析三个平均随访：荟萃分析三个平均随访4-10年的社区队列研究结果，年的社区队列研究结果，NAFLD患者未来新发糖尿病风险是

35、非脂肪肝患者的患者未来新发糖尿病风险是非脂肪肝患者的3.51倍倍6从脂肪肝到从脂肪肝到2 2型糖尿病型糖尿病Hepatology Research 2013;43:5164 7为什么肝脏脂肪沉积可以引起糖代谢异常为什么肝脏脂肪沉积可以引起糖代谢异常1Departm ent of I nternal M edi ci ne,Yal e Uni versi ty School of M edi ci ne,N ew H aven,Connecti cut 06520,USA.2VA Connecti cut H eal thcare System W est H aven,Connecti cut

36、 06516,USA.3N ovo N ordi sk Foundati on Center f or Basi c M etabol i c Research,Uni versi ty of Copenhagen,Copenhagen DK-2200,Denm ark.4Departm ent of Cel l ul ar and M ol ecul ar Physi ol ogy,Yal e Uni versi ty School of M edi ci ne,N ew H aven,Connecti cut 06520,USA.5H ow ard H ughes M edi cal I

37、nsti tute,Yal e Uni versi ty School of M edi ci ne,N ew H aven,Connecti cut 06535-8012,USA.Modern gl obal heal t h care f aces chal l enges t hat are drast i cal l y di f f erent f rom past generat i ons,l argel y owi ng t o t he i ncreas-i ng worl dwi de preval ence of obesi t y.Thi s i s exem pl i

38、 f i ed by a change i n f ocus t o cent re on obesi t y-rel at ed l i ver di sease.Al t hough vi ral hepat i t i s cont i nues t o be an i m port ant heal t h concern,non-al cohol i c f at t y l i ver di sease(NAFLD)i s t he now m ost com m on l i ver di sorder i n t he W est ern worl d,where t he r

39、at es of adul t and paedi at ri c obesi t y have soared t o an est i m at ed 20 30%of t he U S popul at i on1,2.In east and sout h Asi an com m uni t i es,NAFLD i s al so on t he ri se,wi t h est i m at es t hat i t s preval ence reaches as hi gh as 60%i n urban areas3,4.St art l i ngl y,NAFLD has b

40、een f ound t o be hi ghl y preval ent am ong young l ean sout h Asi an Indi ans5,6.A st rong associ at i on bet ween NAFLD and t ype 2 di abet es has been dem onst rat ed:m ore t han 90%of obese pat i ent s wi t h t ype 2 di abet es have NAFLD7.I nsul i n resi st ance i s com m on i n bot h condi t

41、i ons5.Pat i ent s wi t h NAFLD al m ost uni versal l y have hepat i c i nsul i n resi st ance,whi ch i ncreases t he ri sk of i m pai red f ast i ng gl ucose and t ype 2 di abet es5,8 11.In addi t i on,a subset of pat i ent s wi t h NAFLD wi l l devel op non-al cohol i c st eat ohepat i t i s(NASH)

42、wi t h hi st ol ogi cal changes such as st eat osi s,l obu-l ar i nf l am m at i on and/or hepat ocel l ul ar bal l ooni ng12.Around 20%of pat i ent s wi t h NASH wi l l progress t o l i ver ci rrhosi s and l i ver f ai l ure13,14.NASH-associ at ed ci rrhosi s i s now t he t hi rd m ost com m on i n

43、di cat i on f or l i ver t ranspl ant at i on i n t he Uni t ed St at es15.Heal t h pol i ci es t hat can prevent NAFLD and new t reat m ent s t hat can reverse t he di sease wi l l of f er t rem endous benef i t s,i n t erm s of bot h l i ves saved and heal t h-care cost s.Thus,i n t hi s Perspect

44、i ve we wi l l di scuss t he l i nk bet ween hepat i c l i pi d accum ul at i on and hepat i c i nsul i n resi st ance and f ocus on t he rol e of di acyl gl ycerol,a l i pi d m et abol i t e t hat act i vat es novel prot ei n ki naseC i so-f orm s(PKCs)and t hereby i m pai rs i nsul i n si gnal l i

45、 ng,i n t he pat hogenesi s of l i pi d-i nduced hepat i c i nsul i n resi st ance.Al t hough several ot her m echa-ni sm s have been proposed t o expl ai n t hi s associ at i on,t hese al t ernat i ves have been revi ewed el sewhere16.As we wi l l di scuss here,di acyl gl ycerol-i nduced novel PKC

46、act i vat i on has em erged as a com m on m echani sm t o expl ai n t he devel opm ent of i nsul i n resi st ance i n l i ver and skel et al m uscl e i n a vari et y of experi m ent al and cl i ni cal m odel s.M M o ol l e ec cu ul l a ar r m m e ec ch ha an ni i s sm m o of f l l i i p pi i d d-i i

47、 n nd du uc ce ed d i i n ns su ul l i i n n r re es si i s st ta an nc ce e I nsul i n act i on requi res a coordi nat ed,i nt ri cat e rel ay of i nt racel l ul ar si g-nal s,i nvol vi ng m ost l y phosphoryl at i on and dephosphoryl at i on event s.I n t he canoni cal vi ew of hepat i c i nsul i

48、n si gnal l i ng,i nsul i n bi nds and act i vat es t he i nsul i n recept or t yrosi ne ki nase(IRTK),whi ch i n t urn pro-m ot es t yrosi ne ki nase phosphoryl at i on of i nsul i n recept or subst rat es(I RS),m ost i m port ant l y I RS2 i n t he l i ver(Fi g.1)17.Phosphoryl at i on of IRS2 gene

49、rat es bi ndi ng si t es f or Src hom ol ogy 2 dom ai n prot ei ns,i ncl udi ng phosphat i dyl i nosi t ol-3-O H ki nase(PI(3)K)18.The bi ndi ng of PI(3)K t o IRS2 recrui t s phosphat i dyl i nosi t ol-3,4,5-t ri sphosphat e(Pt dI ns(3,4,5)P3),whi ch i n t urn recrui t s Akt19.Under i nsul i n-st i

50、m ul at ed condi t i ons,3-phosphoi nosi t i de-dependent ki nase-1 phosphoryl at es and act i vat es Akt,whi ch i s t hought t o suppress hepat i c gl ucose product i on t hrough t wo key m echani sm s:f i rst,decreased expressi on of gl uconeo-geni c enzym es by phosphoryl at i on and nucl ear exc

51、l usi on of t he f ork-head box prot ei n FOXO1 and i t s pro-gl uconeogeni c t arget s,and second,act i vat i on of gl ycogen synt hase by phosphoryl at i on and i nact i vat i on of gl ycogen synt hase ki nase-3.Al t hough t hi s rel at i vel y l i near const ruct i s usef ul f or i nt errogat i n

52、g i nsul i n si gnal l i ng i n experi m ent al m odel s,i t f ai l s t o capt ure t he i nt erwoven m echani sm s t hat have evol ved t o regul at e hepat i c gl ucose and l i pi d m et abol i sm.For exam pl e,al t hough acut e i nsul i n si gnal l i ng f ol l owi ng a m eal can decrease m essenger

53、 RNA expressi on of gl uconeogeni c enzym es,i t probabl y does not acut el y al t er t he prot ei n l evel s of t hese enzym es.Gl uconeogeni c enzym es are al so convent i onal l y t hought t o be subj ect t o al l ost eri c act i vat i on:acet yl coenzym e A(acet yl-CoA)act i vat es pyruvat e car

54、boxyl ase20,21,and f ruct ose-2,6-bi sphosphat e i nhi bi t s f ruct ose-1,6-bi sphosphat ase22.And,al t hough i nsul i n m i ght act i-vat e gl ycogen synt hesi s,gl ucose i s necessary t o i nhi bi t gl ycogen phos-phoryl ase and ef f ect i vel y prom ot e net hepat i c gl ycogen synt hesi s23,24.

55、The devel opm ent of NAFLD i s st rongl y associ at ed wi t h hepat i c i nsul i n resi st ance.Thi s rel at i onshi p i s m ost apparent when NAFLD i s i nduced i n rat s af t er j ust 3 days of bei ng f ed a hi gh-f at di et.The abi l i t y of i nsul i n t o suppress hepat i c gl ucose product i o

56、n i s di m i ni shed i n t hi s m odel even wi t hout changes i n body wei ght,adi posi t y or m uscl e i nsul i n resi st ance25.Hepat i c i nsul i n resi st ance i n t hi s m odel was associ at ed wi t h i ncreased hepat i c di acyl gl ycerol cont ent and i ncreased t ransl ocat i on of t he pri m

57、 ary novel PKC i sof orm i n l i ver,prot ei n ki nase-C (PKC)26,27,t o t he pl asm a m em brane at whi ch i t was f ound t o bi nd and i nhi bi t t he act i vi t y of t he i nt racel l ul ar ki nase dom ai n of t he i nsul i n recept or.Thi s was associ at ed wi t h reduced i nsul i n-st i m ul at

58、ed phosphoryl at i on of IRS2 and IRS2-associ at ed PI(3)K act i vi t y and phosphoryl at i on of Akt 2.Consequent l y,N No on n-a al l c co oh ho ol l i i c c f fa at tt ty y l l i i v ve er r d di i s se ea as se e a an nd d i i t ts s d do ow w n ns st tr re ea am m s se eq qu ue el l a ae e,h he

59、 ep pa at ti i c c i i n ns su ul l i i n n r re es si i s st ta an nc ce e a an nd d t ty yp pe e 2 2 d di i a ab be et te es s,a ar re e r ra ap pi i d dl l y y g gr ro ow w i i n ng g e ep pi i d de em m i i c cs s,w w h hi i c ch h l l e ea ad d t to o i i n nc cr re ea as se ed d m m o or rb bi

60、 i d di i t ty y a an nd d m m o or rt ta al l i i t ty y r ra at te es s,a an nd d s so oa ar ri i n ng g h he ea al l t th h-c ca ar re e c co os st ts s.D D e ev ve el l o op pi i n ng g i i n nt te er rv ve en nt ti i o on ns s r re eq qu ui i r re es s a a c co om m p pr re eh he en ns si i v v

61、e e u un nd de er rs st ta an nd di i n ng g o of f t th he e m m e ec ch ha an ni i s sm m s s b by y w w h hi i c ch h e ex xc ce es ss s h he ep pa at ti i c c l l i i p pi i d d d de ev ve el l o op ps s a an nd d c ca au us se es s h he ep pa at ti i c c i i n ns su ul l i i n n r re es si i s

62、st ta an nc ce e a an nd d t ty yp pe e 2 2 d di i a ab be et te es s.P Pr ro op po os se ed d m m e ec ch ha an ni i s sm m s s i i m m p pl l i i c ca at te e v va ar ri i o ou us s l l i i p pi i d d s sp pe ec ci i e es s,i i n nf fl l a am m m m a at to or ry y s si i g gn na al l l l i i n ng

63、g a an nd d o ot th he er r c ce el l l l u ul l a ar r m m o od di i f fi i c ca at ti i o on ns s.S St tu ud di i e es s i i n n m m i i c ce e a an nd d h hu um m a an ns s h ha av ve e e el l u uc ci i d da at te ed d a a k ke ey y r ro ol l e e f fo or r h he ep pa at ti i c c d di i a ac cy yl

64、 l g gl l y yc ce er ro ol l a ac ct ti i v va at ti i o on n o of f p pr ro ot te ei i n n k ki i n na as se e C C i i n n t tr ri i g gg ge er ri i n ng g h he ep pa at ti i c c i i n ns su ul l i i n n r re es si i s st ta an nc ce e.T Th he er ra ap pe eu ut ti i c c a ap pp pr ro oa ac ch he es

65、 s b ba as se ed d o on n t th hi i s s m m e ec ch ha an ni i s sm m cocoulul d d al lal l e evivi a at te e ththe e r re el l a at ted ed e ep pi i d de em im i cs cs of of n no on-aln-al cocoh ho ol i l i c c fafatty tty l i l i v ve er r di sease di sease anand d type type 2 2 didi abetabetes.es

66、.T Th he e r ro ol l e e o of f h he ep pa at ti i c c l li i p pi i d ds s i in n h he ep pa at ti i c c i insnsu ul li in n r re es si i s st ta an nc ce e a an nd d t ty yp pe e 2 2 didi a ab be et te es sRachel J.Perry1,Varm an T.Sam uel1,2,K i tt F.Petersen1,3&G eral d I.Shul m an1,3,4,58 4|N A T U R E|V O L 5 1 0|5 JU N E 2 0 1 4PERSPECTI VEdoi:10.1038/naturdoi:10.1038/nature13478e13478 2014 M acm i l l an Publ i shers Li m i ted.Al l ri ghts reservedNature.2014 Jun 5;510(7503):84-91.8高脂饮食