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Kafe 바로가기주관연구기관 | 서울대학교 Seoul National University |
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연구책임자 | 이미옥 |
참여연구자 | 박현성 , 김일용 , 구승회 |
보고서유형 | 최종보고서 |
발행국가 | 대한민국 |
언어 | 한국어 |
발행년월 | 2017-11 |
주관부처 | 미래창조과학부 Ministry of Science, ICT and Future Planning |
등록번호 | TRKO201700017992 |
DB 구축일자 | 2018-03-03 |
키워드 | 비알콜성 지방간염.간암.M1/M2 극성 변화.아디포카인.인슐린 저항성.Nonalcoholic steatohepatitis.Hepatocellularca rcinoma.M1/M2 polarity switch.Adipokine.Insulin resistance. |
DOI | https://doi.org/10.23000/TRKO201700017992 |
1세부
1. M1과 M2로 활성화된 Kupffer cell에서 유전자 발현 pattern을 microarray를 통해 분석하여 heat map 작성, ontology 분석, TF enrichment 분석을 통해 핵심인자 NR1F1과 KLF4를 발굴함
2. NR1F1가 Kupffer cell의 polarity를 M1은 억제하고 M2를 활성화시켜 고지질식이 유도 지방간염 질환을 완화시킴을 마우스 모델에서 확인함
3. NR1F1이 간세포의 암화 단백질 (STAT3)의 활성을 저해시킴을 NR1F1 활성 약물 및 Knocko
1세부
1. M1과 M2로 활성화된 Kupffer cell에서 유전자 발현 pattern을 microarray를 통해 분석하여 heat map 작성, ontology 분석, TF enrichment 분석을 통해 핵심인자 NR1F1과 KLF4를 발굴함
2. NR1F1가 Kupffer cell의 polarity를 M1은 억제하고 M2를 활성화시켜 고지질식이 유도 지방간염 질환을 완화시킴을 마우스 모델에서 확인함
3. NR1F1이 간세포의 암화 단백질 (STAT3)의 활성을 저해시킴을 NR1F1 활성 약물 및 Knockout 마우스에서 확인함
4. 지질 대사체 DHA에 의해 NR1F1이 활성화되고 Kupffer cell의 항염증 반응을 일으켜 NASH를 완화시킬 수 있음을 확인함
5. NR1F1이 간세포에서 Knockout 될 시 Diethylnitrosamine 유도 종양이 크게 증가하는 것을 관찰하여 NR1F1의 종양 억제 기능을 확인함
6. NR1F1이 Kupffer cell의 염증 항상성 유지를 통하여 NASH 단계를 완화시키고 간세포의 종양 증식을 억제함으로써 비만 유도 간암 질환의 핵심 매개체로 작용할 수 있음을 규명
2세부
1. 비만 시 수반되는 저산소 상태의 지방전구세포 (3T3-L1 cells)에서 Wnt10b의 발현이 HIF-2a의존적으로 증가하여 분비가 증가됨
2. 비만지방세포의 비대화는 YAP/TAZ를 증가시키고 Wnt5a의 발현을 증가시킴. Wnt5a는 혈중에 분비되고 간조직에 축적됨
3. 비만 완화제로 흑차의 성분을 평가하고 특허 등록함
4. 지방세포 특이적 Wnt5a 결손 마우스제작
5. 담즙산 (CDCA)에 의한 HIF-1a의 억제하여 대사성 질환 진행 억제제로 활용 가능성 제시
6. 지방줄기세포 조절 히스톤 탈메틸화 효소억제제 특허
3세부
1. 간암 모델동물인 HBx TG 마우스에 고지방, 고탄수화물 식이를 먹여 비만을 유도함으로 간암 발생에 미치는 영향을 조사하고 그 유전자 변화를 연구함.
2. weight cycling 모델에서는 전사체 발현분석을 통해 고지방식이의 급이 여부에 따라 발현이 변화하는 유전자군을 찾았고 이들이 이차면역세포의 활성과 관련됨을 확인함.
3. 비만의 간암 저해인자 발굴을 위해 VLDLR KO 마우스를 활용해서 ER stress 유발과 고지방 식이를 통한 지방간이 발생여부 및 기전을 연구하였으며, Sumoylation에 의한 지방간 경감 기전을 연구함.
4세부
1. HFD에 의한 지방간 유도 모델에서 AAV PKC epsilon RNAi 주입에 따른 지방간 및 인슐린 저항성 감소가 나타나지 않음. --> 기존 모델의 수정 필요.
2. SIK2 KO mouse에서 지방세포 크기 증가 및 macrophage infiltration 증가를 확인함. 지방 세포의 dysregulation에 의한 비알콜성 지방간 형성 및 인슐린저항성을 in vivo에서 검증함.
3. PRMT1 간특이적 유전자 적중 생쥐를 이용하여 PRMT1의 간에서 의 억제는 비알콜성 지방간을 촉진하며, 간섬유화의 가속화 및 비알콜성지방간 유래 간암을 유도함을 확인함.
4. PPP4R3의 간특이적 유전자 적중 생쥐를 이용하여 HFD에 의해 유발된 비알콜성 지방간이 PP4 기능상실에 의해서 가속화되며, 이는 정상적인 unfolded protein response 저해에 따른 ER stress의 과도화에 의해 나타남을 확인함.
5. CRTC2의 간특이적 유전자 적중 생쥐의 에너지 대사 개선 효과 검증을 위하여 본 과제에서 개발된 AAV 기법으로 miR-34a 및 FGF21을 간에서 발현하여 그 기능을 검증함.
(출처 : 보고서 요약문 4p)
Subject 1
(1) Analysis of Kupffer cell polarity in fatty liver/NASH/cirrhosis/HCC specimens
● Increased M1 population and decreased M2 population of Kupffer cells by using high-fat diet (HFD) induced NASH progression in mouse model
● Increased M1 population and decreased M2 population of Ku
Subject 1
(1) Analysis of Kupffer cell polarity in fatty liver/NASH/cirrhosis/HCC specimens
● Increased M1 population and decreased M2 population of Kupffer cells by using high-fat diet (HFD) induced NASH progression in mouse model
● Increased M1 population and decreased M2 population of Kupffer cells in NASH patients by analyzing human patients' clinical database
● We perfomed microarray analysis of M1 or M2 activated Kupffer cells and obtained NR1F1 and KLF4 as key regulator of M1/M2 polarity switch in Kupffer cells through analysis of heat map, ontology, and TF enrichment
● Observation of autophage flux change in NR1F1 regulated hepatocytes
(2) Studies on the pathological factors that determine Kupffer cell polarity
● Inflammation mediators and lipid metabolites regulated Kupffer cell M1/M2 poarity switch. Resistin and Adiponectin activated M1 and M2, respectively. Saturated fatty acids and w-3 polyunsaturated fatty acids activated M1 and M2, respectively.
● Role of NR1F1 in Kupffer cell polarity switch: NR1F1 suppressed M1 Kupffer cells and activated M2 Kupffer cells that attenuated high-fat diet induced liver injury.
● Contruct of NR1F1 Knock-out mouse, Further work for investigation of susceptibility of hepatocellular carcinoma
● Observation of autophage related markers change in NR1F1 regulated hepatocytes
(3) Validation of the determinant found in year 2 in KC polarity switch
● Observation of regulating proliferation by control activity of STAT3 through NR1F1 activation
● Microarray analysis of NR1F1 agonist and inverse agonist treated Kupffer cells: Analysis of regulation of M1/M2 Kupffer cells polarity switch by NR1F1
● Identification of role of NR1F1 in mitophagic pathway using high-fat diet NASH mouse model
(4) Validation to key regulators of Kupffer cell polarity for developing therapeutic target against HCC
● Observation of regulation of oncogenic proteins (STAT3) by NR1F1 ligand and Knockout
● Identification of NR1F1 Knockout in hepatocytes and Kupffer cells to change proliferation and anti-inflammation that results in exacerbation to Obesity-induced HCC
● Analysis for expression level of key regulators of Kupffer cells in public database
(5) Establishment to new therapeutic strategy for attenuation of obesity-induced HCC using NR1F1 ligand
● Observation of exacerbation to NASH by myeloid-specific Knockout of NR1F1
● Verifying the effect of DHA to enhance NR1F1 function and M2 polarization of Kupffer cells that improve progression of NASH
● Observation of enhanced tumorigenesis in the liver-specific Knockout of NR1F1
Subject 2
(1) Changes in expressions of adipokines in obese adipose tissues
● Development of big data for expression of adipokines (Microarray, histone ChIp-seq analyses)
● Expression of Wnt10b: Wnt10b an anti-adipogenic factor from preadipocyte is induced bt hypoxia in HIF-2a but not HIF-1a dependent manner (JBC correspondence 2013: IF 4.651)
● Expression of Pref-1: Pref-1, an anti-adipogenic factor and maker for preadipocytes is dinduced by hypoxia. Prolonged HFD mouse have higher level of Pref-1, but it is not secreted from obese adipose tissue but from other organ. Increment of Pref-1 in obese individual inhibit adipogenesis which is required for maintain healthy adipose tissue to prevent severe hypertrophy.(BBA-Mol Cell Res, correspondence 2017-revision: IF 5.1)
● Expression of Wnt5a : Hypertrophic adipocytes increase expression of Wnt5a in YAP/TAZ dependent manner. Prolonged HFD mouse have higher level of Wnt5a protein in serum and liver tissue. However liver failed to increased it mRNA, suggesting that Wnt5a secreted from obese adipocytes accumulated in liver tissue to cause inflammation. we pursue this study further.
● Anti-obesity effect of black tea: Black tea reduced weight and obese fat contents without reducing expression of PPARγ and without inhibiting adipogenesis. These characteristics are beneficial to increase hyperplasia but not hypertrophy of adipocytes. Since hypertrophy aggravate in increase inflammation (Archives of Pharmacal Research, correspondence : 2016 IF= 2.49) (Korean Patent registered)
(2) To characterize adipokines causes Liver diseases and metabolic abnomalities
● Wnt5a secreted from obese adipose to reach in liver: Prolonged HFD increased secretion from obese adipose tissues in serum and accumulated in liver. The findings that liver do not increased mRNA of Wnt5a and that Wnt5a is not detected in isolated hepatocytes but in liver tissues suggest that wnt5a from obese adipose tissue reached to liver and accumulated. The finding that recombinant Wnt5a increased inflammatory cytokines in isolated liver cells suggested that Wnt5a from obese adipose increases inflammation in liver. We succeed to make adipcyte-specific Wnt5a KO mouse. We will further study this hypothesis in vivo (Further study)
● HIF-1a inhibitory function of Cholic acids (CDCA) : HIF-1a contributes obese induced metabolic diseases, liver diseases by increasing expression of inflammatory adipokines. We found that CDCA inhibits HIF_1a suggesting that less toxic bile acid deivative can be use to improve liver diseases and metabolic diseases by inhibiting HIF-1a (PLOS ONE correspondence : 2015 IF= 3.234)
① HIF-1 alpha active agent (US Patent registered)
(3) Impact of hypoxic condition of obese adipose tissue on adipose derive stem cells.
● Histone methylation-Epigenetics : Human adipose derived stem cells (Adsc) were widely used for stem cell therapy and important for maintain homeostasis of adipose tissues. To investigate how obesity influence stemness of ADSC we performed genome wide analyses of whole genomes of hypoxia exposed ADSC by perfoming histone ChIP analyses and micro array. We predicted possible TFs which located in genomic region where histone methylation will changes by hypoxia (Nucl Acid Res correspondence, 2017-in press IF=10.12)
● Clioquinol and its derivatives as inhibitors of JMJD3 (Korean Patent registered)
● Histone methylation reprogrammin of senescence induing INK4a locus (Febs Lett correspondence 2016 IF = 3.519)
Subject 3
(1) Identification of onset of obesity-Induced Hepatocellular Carcinoma using HBx TG Mouse
● Obesity induction by high fat and high carbohydrate diet in HBx TG mice
● Conference poster presentation 1
(2) Physiological changes due to weight cycling and gene discovery for obesity
● Obesity physiological changes according to the level of high fat diet
● Identification of genes whose expression changes depending on whether or not the high-fat diet is fed
● SCI paper 1 (Int J Obes, 2017, 11)
(3) Causal relationship between VLDLR-induced fatty liver induction and VLDLR abnormalities
● Liver VLDLR Induced Factor Induced by Fatty Liver Induction
● Controlling fatty liver induction and VLDLR abnormality through VLDLR KO mice
● Characteristic analysis of Macrophage in VLDLR KO mice
● SCI paper 1 (Mol Cell Biol, 2017, 08)
(4) Studies on the regulation of fatty liver by SUMOylation
● Identification of signaling pathways associated with fatty liver control by SUMO regulators
● SCI paper 1 (Diabetes, 2016, 09)
Subject 4
● Identification of the role of ERRgamma on hepatic glucose metabolism and insulin resistance (Diabetes 2013, corresponding author)
● Review paper regarding hepatic glucose metabolism (BMB Reports 2013, corresponding author)
● Identification of the role of PRMT6 on hepatic glucose metabolism (Science Signaling 2014, corresponding author)
● Identification of the role of SIK2 on lipid metabolism and insulin signaling (Diabetes 2014, corresponding author)
● Identification of the role of SIK1 on insulin secretion from pancreatic beta cells (Diabetes 2015, corresponding author)
● Identification of the role of ERRgamma on hepatic glucose metabolism (Diabetes 2016, corresponding author)
● Identification of the role of BI-1 on hepatic insulin signaling (Scientific Reports 2016, corresponding author)
● Review paper regarding hepatic glucose metabolism (Experimental and Molecular Medicine 2016, corresponding author)
● Identification of the novel role of CRTC2 in miR-34a-FGF21-mediated control of obesity and insulin resistance (Nature Communications 2017(in press), corresponding author)
● Identification of the novel role of CRTC2 in GLP-1 secretion (FASEB J 2017(in press), corresponding author)
● Establishment of the NAFLD-mediated HCC mouse models by using PRMT1 liver-specific knockout mice (In preparation)
● Establishment of the mouse models of fatty liver and insulin resistance by using PPP4R3b liver-specific knockout mice (In preparation)
(출처 : SUMMARY 9p)
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연구목표(Goal) : | - |
연구내용(Abstract) : | - |
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