CN104056271A - Functions and application of TNF (tumor necrosis factor) receptor associated factor 5 (TRAF5) in treatment of fatty liver and type 2 diabetes mellitus - Google Patents

Abstract

The invention discloses functions and application of TNF (tumor necrosis factor) receptor associated factor 5 (TRAF5) in treatment of fatty liver and type 2 diabetes mellitus. Studies on a TRAF 5 gene by a high-fat diet (HFD) induced model discover that both the body weight and fasting plasma glucose level of an HFD bred TRAF gene knock-out mouse are lower than those of a WT mouse; glucose tolerance tests by intraperitoneal injection discover that the glucose tolerance of the TRAF5 gene knock-out mouse is remarkably reinforced; results of on liver gross appearance, liver weight, liver/body weight ratio and lipid component pathological staining indicate that the TRAF5-KO mouse fatty liver lesion in the HFD group is remarkably improved, the lipid accumulation is remarkably reduced, and the TRAF5 gene knock-out has the effects of remarkably improving fatty acid and type-II diabetes mellitus. Against the effects, the TRAF5 gene knock-out can be used as a medicinal target for screening and treating fatty liver and/or type-II diabetes mellitus, and the inhibitor of the TRAF5 gene knock-out can be used for preparing medicaments for treating fatty liver and/or type-II diabetes mellitus.

Description

The function and application of TNF receptor associated factor 5 (TRAF5) in treatment fatty liver and type Ⅱdiabetes mellitus

Technical field

The invention belongs to function and the application of gene, be particularly related to a kind of TNF receptor associated factor 5(TRAF5) as drug targets, in the medicine that screens treatment fatty liver and type Ⅱdiabetes mellitus disease, apply, and the inhibitor of TRAF5 is applied in the medicine of preparation and/or screening prevention, alleviation and/or treatment fatty liver and type Ⅱdiabetes mellitus disease.

Background technology

Along with the aged's increase, the life of urbanization and the change of life style, the Developmental and Metabolic Disorder crowds such as obesity, non-alcoholic fatty liver disease, metabolism syndrome and diabetes increase severely, the existing important harm that has become global public health.Diabetes are chronic metabolic disease of a kind of serious harm human health.Twenty or thirty is in the past in year, and diabetics quantity is double, to the health of global human, is a very serious threat.In 2010, in world wide, 2.85 hundred million populations suffer from diabetes, wherein 90% patient is type Ⅱdiabetes mellitus (type 2 diabetes mellitus, T2DM), the quantity that expects the year two thousand thirty patient will be increased to 4.39 hundred million, this means that in global 20-79 year adult, will have 7.7% is diabetics.Current child, in teenager and Young Patients, type Ⅱdiabetes mellitus and type Ⅱdiabetes mellitus sickness rate in early stage increase severely, and this also means that the morbidity crowd in following diabetes will expand, and difficulty of prevention and cure will increase.

Diabetes disease itself adds its is fearful and be difficult for reversing complication on patient's quality of life and life and health impact greatly simultaneously, is also the important problem of current clinical and research circle.Chronic complicating diseases of diabetes is to cause the lethal main cause disabling of diabetics, not only involves important organ and the tissues such as cardiovascular and cerebrovascular vessel, kidney, retina, nerve, and liver is also one of its important target organ.Liver is one of topmost organ of carbohydrate metabolism, is the maincenter of substance metabolism, and it has many important physiological functions, as the synthetic of glucose with decompose, and lipid synthesis and decomposition, the synthetic and secretion of bile etc.Liver is human body biochemical plant, and lipid is synthesized by liver and exports.Along with the prolongation of diabetic duration, danger and lesion degree thereof that hepatic lesions occurs also increase thereupon.Diabetic hepatic injury refers to liver histological and the changes of function that diabetes cause, is a kind of chronic complicating diseases of diabetes.The early diagnosis of diabetes, control chronic complicating diseases of diabetes is particularly important to relieve patient ' s burden.

Tumor necrosis factor (TNF) receptor associated factor (the TNF receptor-associated factor of family, TRAF) be the similar adaptin of a class formation, as endocellular signal molecule, in TNFR superfamily, Toll sample/white interleukin-1 receptor (Toll/IL-1 receptor, TIR) superfamily and the stream signal conduction of RIG sample receptor (RLR) family, play a significant role.In mammal, TRAF family has 7 members at present, is respectively TRAF1-7.The C-terminal characteristic TRAF domain that TRAF comprises about 230 amino acid longs, mediation TRAF albumen forms homology or heterodimer or in conjunction with other adapter molecules and signal transduction molecule.Nearly N end (TRAF-N) two subdomains that this domain can be divided into the nearly C end (TRAF-C) of high conservative and differ greatly, this species diversity decision TRAF under specific environment and cell type in conjunction with different receptors or signal activator.Except TRAF1, TRAF2-7 also comprises the N-terminal ring structure territory (RING finger domain) of a high conservative.TRAF has the important biomolecules such as modulate host defence, inflammation and autoimmune and learns function, and plays a significant role at cell differentiation, propagation, apoptosis.TRAF5 is considered to regulate and control the receptor of TNFR superfamily, and it may be the key molecule of reply viral infection natural response.TRAF5 plays a significant role in the activation of the kinase whose activation of c-Jun of LMP1 mediation and the p38 MAPK of induction; Thereby can activate NF-κ B by CD40 and tumor necrosis factor β receptor; In bone-marrow-derived lymphocyte, can also regulate and control TLR signal path; Also can participate in T cell proliferation after viral infection and the activation (1,2,3) of natural immunity signal path and the JNK in atherosclerosis.Research shows that TRAF5 knock out mice can reduce blood brain barrier (BBB) and destroy and inflammation, thus the damage (4) that protection cerebral ischemia re-pouring causes; In the myocardial hypertrophy that TRAF5 causes at aorta arch constriction by MEK-ERK1/2 signal path, play a significant role (5), and the effect of TRAF5 in fatty liver, diabetes there is no report.

List of references:

1. Shirakata M, Imadome KI, Okazaki K, Hirai K. 2001. Activation of TRAF5 and TRAF6 signal cascades negative ly regulates the latent replication origin of Epstein–Barr virus through p38 mitogen‐activated protein kinase. J Virol 75:5059–5068.

2. Kraus ZJ, Nakano H, Bishop GA. 2009. TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proc Natl Acad Sci USA 106:17140–17145.

3. Buchta CM， Bishop GA. TRAF5 negatively regulates TLR signaling in B lymphocytes. J Immunol. 2014 Jan 1;192(1):145-50.

4. Wang L, et al. Tumor necrosis factor receptor-associated factor 5 is an essential mediator of ischemic brain infarction. J Neurochem(2013), 126(3):400-14.

5. Bian Z et al. Disruption of tumor necrosis factor receptor associated factor 5 exacerbates pressure overload cardiac hypertrophy and fibrosis. J Cell Biochem(2014), 115(2):349-58。

Summary of the invention

For solving defect and the deficiency of above-mentioned prior art, the object of the present invention is to provide the mutual relation between a kind of expression of TRAF5 gene and fatty liver, type Ⅱdiabetes mellitus, provide one be used for the treatment of fatty liver and/or type Ⅱdiabetes mellitus the new purposes of target gene TRAF5, and then TRAF5 gene is applied to the treatment of fatty liver and/or type Ⅱdiabetes mellitus.

Object of the present invention is achieved through the following technical solutions:

It is experimental subject that wild type C57 mice and TRAF5 knock out mice are take in the present invention, the Mice model of obesity of inducing by high fat diet (diet induced obesity, DIO) function of research TRAF5 gene, found that high lipid food (High fat diet, the body weight of the TRAF5 knock out mice of HFD) raising and fasting blood glucose level, all lower than matched group WT mice, further find that by lumbar injection glucose tolerance experiment TRAF5 knock out mice obviously strengthens the tolerance of glucose.From mouse liver general appearance, liver weight, liver/weight ratio and lipid components pathological staining result etc., all illustrate that the TRAF1 KO mice fatty live lesions of HFD group (Highfat diet, high fat diet) is clearly better, accumulation of lipid significantly reduces.This shows that TRAF5 gene knockout can significantly improve the generation of fatty liver, type Ⅱdiabetes mellitus, TRAF5 gene has the effect that worsens fatty liver, type Ⅱdiabetes mellitus, and novel targets and the New Policy of for research, preventing and treating fatty liver, type Ⅱdiabetes mellitus provide theoretical foundation and Clinical Basis.

Therefore, TRAF5 gene can be used as drug target, builds In vitro cell model or the animal model of TRAF5 gene overexpression, for screening the medicine of prevention, alleviation and/or treatment fatty liver, type Ⅱdiabetes mellitus; TRAF5 gene also can be used as the target gene in gene therapy, design and prepare medicine and/or the biological reagent of prevention, alleviation and/or treatment fatty liver, type Ⅱdiabetes mellitus, by technique for gene engineering, reach the object of prevention, alleviation and/or treatment fatty liver, type Ⅱdiabetes mellitus.For example take TRAF5 as target gene, and the double-stranded siRNA that design can disturb TRAF5 to express, after synthesizing, is injected into the method that human body disturbs by RNA and makes TRAF5 gene silencing treat fatty liver, type Ⅱdiabetes mellitus by chemical method; The mutant that can also design and build TRAF5, enters cell after injection, the effect substrate of competition TRAF5 original shape, thus the function of inhibition TRAF5 plays therapeutic purposes; In addition, can also take TRAF5 as shot design micromolecular compound inhibitor, utilize In vitro cell model or the animal model of TRAF5 gene overexpression, by screening, find wherein can specificity to suppress the molecule of TRAF5, thereby provide new therapeutic molecules for the treatment of fatty liver, type Ⅱdiabetes mellitus.

For the above-mentioned functions of TRAF5, provide TRAF5 application in the medicine of screening the liver protecting function as drug targets.

For the above-mentioned functions of TRAF5, provide TRAF5 as drug targets screening prevention, alleviate and/or treatment fatty liver and or the medicine of type Ⅱdiabetes mellitus in application.

For the above-mentioned functions of TRAF5, the application of the inhibitor that TRAF5 is provided in the medicine of preparing the liver protecting function.

For the above-mentioned functions of TRAF5, the inhibitor that TRAF5 is provided preparation prevention, alleviate and/or treatment fatty liver and or the medicine of type Ⅱdiabetes mellitus in application.

A medicine for liver function protecting, the inhibitor that comprises TRAF5.

Treat fatty liver and or the medicine of type Ⅱdiabetes mellitus, the inhibitor that comprises TRAF5.

The inhibitor of described TRAF5 is preferably the siRNA of TRAF5 gene, the rna interference vector of TRAF5 gene, and the antibody of TRAF5 and other can suppress a kind of in inhibitor that TRAF5 expresses.

The present invention has following advantage and effect with respect to prior art:

(1) the present invention finds the new function of TRAF5 gene, and TRAF5 gene can worsen the effect of fatty liver, type Ⅱdiabetes mellitus disease.

(2) function in worsening fatty liver, type Ⅱdiabetes mellitus based on TRAF5 gene, is the drug provision target of fatty liver, type Ⅱdiabetes mellitus.

(3) medicine that the inhibitor of TRAF5 can be used for preparing liver function protecting and treats fatty liver, type Ⅱdiabetes mellitus.

Accompanying drawing explanation

Fig. 1 is body weight, the fasting glucose result figure of WT and TRAF5-KO mice; A is Mouse Weight result figure; B is fasting blood glucose level cartogram (* *: p < 0.01 vs WT NC group, #:p < 0.05 vs WT HFD group, ##:p < 0.01 vs WT HFD group).

Fig. 2 is that WT and TRAF5-KO mice pass through lumbar injection glucose tolerance result figure; A is by the horizontal cartogram of different time points mouse blood sugar after lumbar injection glucose; B is each group glucose tolerance in mice area under curve (area under the curve, AUC) comparison diagram (* *: p < 0.01 vs WT NC group, ##:p < 0.01 vs WT HFD group).

Fig. 3 is the liver general appearance result figure of TRAF5-KO and WT mice; A is liver result figure substantially; B is the own weight ratio Data-Statistics of liver weight, liver weight and mice block diagram (##:p < 0.01 vs WT HFD group).

Fig. 4 is liver organization HE and the oil red O stain figure of WT and TRAF5-KO mice.

The specific embodiment

Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.

Animal for research and raising:

Laboratory animal kind, sex, age in week and source: C57BL/6(WT) mice and TRAF5-KO mice, male, 8 week age.C57BL/6 mice is purchased from China bio tech ltd, Fukang, Beijing; (TRAF5-KO, purchased from Japanese RBRC company, article No.: RBRC02573) for TRAF5 knock out mice.

Laboratory animal feed formula: high lipid food (High fat diet, HFD) (purchased from China bio tech ltd, Fukang, Beijing, article No. D12942): percent of calories: protein 20%, carbohydrate 20%, fat 60%; Total heat mass ratio 5.24kcal/g.Low fat feedstuff (Normal chow, NC) (purchased from China bio tech ltd, Fukang, Beijing, article No. D12450B): percent of calories: protein 20%, carbohydrate 70%, fat 10%; Total heat mass ratio 3.85kcal/g.

Animal feeding and environmental condition: all experiment mices are all raised at the SPF of Wuhan University angiocardiopathy institute level Animal House (credit number: SYXK(Hubei Province): 2009-0053).Alternately illumination in every 12 hours, 24 ± 2 ℃ of temperature, humidity 40-70%, the mice feed of freely drinking water.

Embodiment 1 mice fatty liver, type Ⅱdiabetes mellitus model (diet induced obesity, DIO) obtain

(1) laboratory animal grouping: select 8 week age, male, WT mice and TRAF5-KO mice, give respectively with two kinds of special feedstuff D12942 high lipid foods (High fat diet, HFD) and D12450B low fat feedstuff (Normal chow, NC) and raise, it is WT NC group, KO NC group, WT HFD group, KO HFD group is totally 4 groups.

(2) high lipid food guidance model operating process:

Adopt WT and KO mice, set up DIO model, carry out phenotype correlation analysis, define the effect of TRAF5 gene pairs fatty liver, type Ⅱdiabetes mellitus performance.Select 8 week age, male, WT mice and TRAF5-KO mice, give respectively and two kinds of special feedstuff D12942 high lipid foods and D12450B low fat feedstuff are raised, i.e. WT NC group, and KO NC group, WT HFD group, KO HFD group is totally 4 groups.Equal itemized record mice food ration weekly, mice on an empty stomach body weight and fasting glucose every detection in 4 weeks 1 time.Test the 18th week, carry out lumbar injection glucose experiment (IPGTT), to evaluate mice body to glucose-tolerant ability.Within the 20th week, draw materials in whole end, takes out mouse liver and take pictures, and weighs, and then a part is placed in fixing or O.C.T frozen section embedding medium (the Tissue Freezing Medium) embedding of formalin and uses as pathological analysis.

Embodiment 2 Mouse Weights, determination of blood glucose level

(1) mice empty stomach body weight, appetite detects

1. fasting: 8:00 will treat experiment mice fasting (can't help water) in the morning, and afternoon, 2:00 started experimental implementation.

2. weigh: at the 0th week, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, weigh respectively, a plastics keg is placed on dynamic electron balance, pick up mice, put into and weigh keg, measure body weight record data.Forage volume detects: after having operated wait weighing, to mice, add feedstuff, and on dynamic electron balance, record the forage volume of mice.

(2) fasting blood glucose level test experience

By the mice of need experiment from the morning 8:00 to fasting (can't help water) between afternoon 2:00, i.e. fasting started experimental implementation after 6 hours.

1. blood glucose meter is prepared: and inspection blood glucose meter (Johnson Co., ONETOUCH) battery, by right-side switch, reagent paper is correctly put into left side slot, the numeral of screen display and blood sugar test paper bar respective code, shows the pattern of bleeding subsequently, and prompting blood glucose meter enters state to be measured.

2. fixing mice: the right hand is grabbed Mus tail, and left hand is held a towel, by towel doubling, pinches towel fold position with thumb and forefinger, and Mus head and health are wrapped into the towel in palm, and thumb and forefinger are being fixed Mus root of the tail portion.

3. cut tail: eye scissors cutting Mus tail apart from Mus tail end 0.1-0.2cm place, treats that drop of blood flows out voluntarily rapidly.

4. blood sugar test: blood glucose meter reagent paper edge is touched to drop of blood, and blood immerses reagent paper, blood glucose meter countdown shows reading for 5 seconds.

The evaluation index of type Ⅱdiabetes mellitus injury severity score mainly comprises the levels such as body weight, blood glucose, change of blood sugar result as shown in Figure 1, WT mice is after giving and raising with HFD feedstuff, since the 4th week body weight apparently higher than its NC feedstuff group, after raising with the TRAF5-KO mice HFD feedstuff of 20 weeks and NC feedstuff, the WT Mouse Weight that is starkly lower than HFD group since the TRAF5-KO Mouse Weight of the 4th week HFD group, is continued until the 20th week (seeing Figure 1A); The mice of detect finding in HFD group through fasting glucose from the fasting blood glucose level of the 4th week, 8 weeks, 12 weeks, 16 weeks, 20 weeks obviously more corresponding NC matched group raise, and the TRAF5-KO mice fasting blood glucose level of HFD group will be starkly lower than WT mice fasting blood glucose level (seeing Figure 1B).Show to knock out after TRAF5 gene can appreciable impact the carbohydrate metabolism stable state of mice under HFD raising state, the decapacitation of TRAF5 clpp gene significantly improves the carbohydrate metabolism stable state of mice, and these results show that TRAF5 induces in the type Ⅱdiabetes mellitus model causing and plays an important role at high fat.

Embodiment 3 glucose tolerance experiments (intraperitoneal glucose tolerance test, IPGTT)

Test the 18th week, carry out lumbar injection glucose experiment (IPGTT), to evaluate mice body to sugared tolerance.

(1) before surveying blood glucose, first measure the empty stomach body weight of mice, according to 10 μ L/g, calculate the volume injected of glucose.

(2) fasting glucose while first detecting before glucose sugar injection 0 minute, after detecting rapidly through lumbar injection Glucose Liquid.

(3) lumbar injection operational approach: 1. fixing mice; Pick up mice, the little finger of toe of left hand and nameless tail of grabbing mice, another three fingers are caught the cervical region of mice, make the head of mice downward, and mouse web portion is fully exposed.2. inserting needle location and injection: from the right hand syringes of abdominal part one side inserting needle, by the most advanced and sophisticated angle at 45 ° with mouse web portion, inserting needle, pumpback, during injection, syringe needle is walked a bit of distance in subcutaneous abdomen, through after ventrimeson, at abdominal part opposite side, enters abdominal cavity, injected after medicine, slowly extract syringe needle, and slightly rotate syringe needle, prevent leakage.

(4) respectively at 15 minutes, 30 minutes, 60 minutes, 120 minutes points after lumbar injection, cut tail and survey mouse blood sugar value, and record blood glucose numerical value and detection time.

Further by lumbar injection glucose tolerance experiment (intraperitoneal glucose tolerancetests, IPGTT) assess and respectively organize the disposal ability of mice to glucose, experiment the 18th week, after glucose by injection 1.0g/kg body weight, WT mice and the TRAF5-KO mouse blood sugar level of HFD group increase severely and reach peak value at 15 minutes points, along with passage of time is to injecting latter 60 minutes, two groups of mouse blood sugar levels decline a little, but still in higher than fasting blood glucose level (0 minute time blood glucose), in the time of 2 hours, return to fasting blood glucose level, and TRAF5-KO mouse blood sugar level is from 0 minute to 2 hours always in the blood sugar level lower than WT mice (Fig. 2 A).Respectively organize mouse blood sugar area under curve (area under the curve, AUC), the AUC that finds WT mice HFD group is significantly higher than NC group, AUC(Fig. 2 B that the AUC of TRAF5-KO HFD group significantly organizes lower than WT HFD), show that TRAF5 gene knockout can significantly promote carbohydrate metabolism stable state.

Embodiment 4 liver general appearance and liver organization lipid components are measured

(1) last liver organization is drawn materials eventually

1), after mice is weighed, de-neck is put to death rapidly.The fixedly mice that lies on the back, with distilled water by mice chest, abdominal part hair wet.

2) with a tweezers clamp mouse web portion center skin, along abdominal part center, to head, cut off skin to xiphoid-process, caudad cut off skin, successively expose subcutaneous fascia, muscle etc., open abdominal cavity, fully expose each internal organs.

3) find rapidly and take off the liver of mice, the liver specimens of taking off is placed on sterile gauze, wipe away remained blood in dry liver surface, liver is placed in to sterile petri dish, take pictures rapidly, weigh.

4) paraffin specimen: cutting part liver, to be placed in 10% neutral formalin fixing.Freezing specimen: cut part liver, be placed in the tinfoil mould embedding of OCT, be placed on cryofixation on dry ice.

2. liver organization is processed and pathological staining related experiment

1) liver dehydration, transparent, waxdip

Cut in the embedding frame that the part lobe of the liver fixing in 10% neutral formalin is organized in labelling, at low discharge flowing water, rinse more than 30 minutes.According to following flow process, following program is set on machine, 1. dehydration: 75% ethanol (45 minutes) → 75% ethanol (45 minutes) → 85% ethanol (45 minutes) → 85% ethanol (45 minutes) → 95% ethanol (45 minutes) → 95% ethanol (45 minutes) → anhydrous alcohol (1 hour) → anhydrous alcohol (1 hour); 2. transparent: dimethylbenzene (1 hour) → dimethylbenzene (1 hour); 3. waxdip (65 ℃): paraffin (1 hour) → paraffin (1 hour).After treating that tissue rinses, the embedding frame that comprises tissue is put in machine basketry, started said procedure.After said procedure completes, take out organization embedding frame and send pathology chamber investing tissue, cleaning robot is standby simultaneously.

2) liver tissue slices

Use microtome section (slice thickness 5 μ m).

3) liver organization hematoxylin-eosin (HE) dyeing

By liver organization paraffin section put into 65 ℃ of baking ovens (30 minutes) → dimethylbenzene (5 minutes * 3 times) → 100% ethanol (1 minute) → 90% ethanol (1 minute) → 70% ethanol (1 minute) → distillation washing → haematoxylin (5 minutes) → tap water wash away loose colour → 1% hydrochloride alcohol (1 to 3 second) in section → wash from the beginning several under → short blue liquid (the sodium bicarbonate 0.35g of Scott, magnesium sulfate 2g, distilled water 100mL) under (1 minute) → wash is from the beginning several → Yihong (1 minute) → distilled water washes away loose colour → 70% ethanol → 90% ethanol → 100% ethanol (30 seconds * 3 times) → dimethylbenzene (2 minutes * 3 times) → mounting when dimethylbenzene is not dry in section once once, take pictures.

4) liver organization oil red O stain

1. by freezing liver tissue slices in fume hood air-dry 30 minutes, 4% paraformaldehyde was fixed 10 minutes; Be placed in distilled water and slightly wash 10 minutes, the paraformaldehyde showing to remove tissue.

2. with 60% isopropyl alcohol, process 1 minute.

3. use the oil red O(sigma of company, article No. O0625,0.5 gram/100mL of concentration, 100% isopropyl alcohol) dye 30 minutes.

4. after with 60% isopropyl alcohol 1 minute * 3 times, until clean background.

5. use the light transfect cell core of Mayer ' s haematoxylin dye liquor (5).

6. water rinse, short blue in rare lithium carbonate aqueous solution, fully washes, and is washed to nucleus oil blackeite.

7. use glycerin gelatine mounting, take pictures.

As shown in Figure 3, by substantially drawing materials and take pictures, the liver volume of the TRAF5-KO mice observing in HFD group is slightly little compared with the liver of the WT mice of HFD group, and TRAF5-KO mouse liver color and luster is redder, oils and fats less (as Fig. 3 A) for liver general appearance measurement result.The TRAF5-KO mice of the HFD group WT mice low (as Fig. 3 B) no matter liver weight or liver weight and the body weight ratio of mice own are all organized compared with HFD.Further by tissue slice, carry out HE and oil red O stain, micro-Microscopic observation is respectively organized mouse liver and is organized under high fat diet raising condition significant pathological change has occurred.By liver, HE dyes, can observe under HFD raising condition, WT mice and TRAF5-KO mouse liver are organized all lipidosis, hepatocyte generation steatosis, vacuolation and the fusion that can see NC group mice are linked to be lamellar, liver cell form is almost destroyed completely, and the hepatocyte form comparatively complete (on Fig. 4) of TRAF5 KO group mice.By liver oil red O stain, detect lipid in hepatic tissue, the hepatic portal vein of the WT mice that can find in HFD group is large stretch of red around, a large amount of lipidosiss is described, the hepatic portal vein of the TRAF5-KO mice of organizing at HFD has less lipidosis, two groups of mice lipidosiss minimum (as under Fig. 4) of raising at NC feedstuff around.The fatty liver of these presentation of results TRAF5-KO knock out mice obviously improves.

The above results shows that fatty liver, type Ⅱdiabetes mellitus that TRAF5-KO mice occurs under the induction of HFD obviously take a turn for the better than WT group mice.These results show that TRAF5 gene can significantly promote carbohydrate metabolism disturbance, promote liver lipid to form and fatty liver formation.Presentation of results TRAF5 gene of the present invention has important deterioration effect in fatty liver, type Ⅱdiabetes mellitus disease model.

Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.

Claims (7)

1.TRAF5 is the application in the medicine of screening the liver protecting function as drug targets.

2.TRAF5 as drug targets screening prevention, alleviate and/or treatment fatty liver and or the medicine of type Ⅱdiabetes mellitus in application.

The application of the inhibitor of 3.TRAF5 in the medicine of preparing the liver protecting function.

4. a medicine for the liver protecting function, is characterized in that: the inhibitor that comprises TRAF5.

The inhibitor of 5.TRAF5 preparation prevention, alleviate and/or treatment fatty liver and or the medicine of type Ⅱdiabetes mellitus in application.

6. prevention, alleviate and/or treatment fatty liver and or the medicine of type Ⅱdiabetes mellitus, it is characterized in that: the inhibitor that comprises TRAF5.

7. according to the application described in claim 3 or 5 or the medicine described in claim 4 or 5, it is characterized in that: the inhibitor of described TRAF5 comprises siRNA, the rna interference vector of TRAF5 gene, the antibody of TRAF5 of TRAF5 gene.