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Novel Roles of SREBP1c in the Regulation of Compensatory Responses of Pancreatic β cells and Cellular Senescence in Adipocytes : 췌장 베타세포 보상작용 및 지방세포 노화현상을 매개하는 SREBP1c의 역할 연구

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dc.contributor.advisor김재범-
dc.contributor.author이궁-
dc.date.accessioned2021-11-30T04:47:25Z-
dc.date.available2022-09-01T21:00:07Z-
dc.date.issued2021-02-
dc.identifier.other000000165567-
dc.identifier.urihttps://hdl.handle.net/10371/175980-
dc.identifier.urihttps://dcollection.snu.ac.kr/common/orgView/000000165567ko_KR
dc.description학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 생명과학부, 2021. 2. 김재범.-
dc.description.abstractIn the progress of obesity, metabolic organs undergo rapid and dynamic changes to maintain energy homeostasis. For instance, there is a significant rise in pancreatic β cell number, as well as enhanced function, to compensate for increased insulin demand in obesity. Moreover, white adipose tissue suffers hyperplasia, hypertrophy, and inflammatory responses in obesity. Emerging evidence indicates that SREBP1c participates in dynamic responses of metabolic organs in obesity. Nevertheless, the roles of SREBP1c in pancreatic islets and adipose tissue are largely unclear.
In the present study, I have suggested that SREBP1c could serve as a crucial player in regulating compensatory responses of pancreatic β cells and adipocyte senescence in obesity. In pancreatic islets, SREBP1c contributed to β cell mass expansion and elevated serum insulin levels to compensate for increased insulin demands in obesity. In β cells, SREBP1c promoted the expression of cell-cycle genes and increased β cell proliferation via its novel target gene, PAX4. Moreover, transplantation of SREBP1c overexpressing islets restored insulin levels and alleviated hyperglycemia in streptozotocin-induced diabetic animals. These data propose that pancreatic SREBP1c is a pivotal player in mediating β cell compensatory responses in obesity.
In addition, I have discovered that SREBP1c would regulate adipocyte senescence in obesity. Adipocytes were susceptible to senescence due to diminished DNA damage responses in obesity. In this process, it is likely that SREBP1c would participate in the DNA repair process by augmenting PARP1 activity, independent of lipid metabolism. Unexpectedly, downregulation of SREBP1c expression in obese adipocytes induced genomic instability and cellular senescence. In accordance with these, SREBP1c knock-out (KO) mice exhibited an increased proportion of senescent adipocytes and aggravated senescence-induced inflammatory responses in white adipose tissue. These data delineate a novel role of SREBP1c in maintaining genomic integrity, cellular senescence, and metabolic homeostasis in adipocytes.
Taken together, I would like to propose that SREBP1c is an important player in both compensatory responses of β cells and cellular senescence in obese adipocytes. As this study provides a clue to understand how SREBP1c modulates various biological processes beyond regulating lipid metabolism, it is likely that appropriate regulation of SREBP1c and its downstream signaling would be promising targets for whole body energy homeostasis against metabolic insults.		-
dc.description.abstract비만은 개체 수준의 에너지대사 변화를 포함하여 여러 대사기관들의 변화를 야기한다. 예를 들어,비만 시 높아진 혈당을 낮추기 위해 췌장 베타세포는 증식 및 인슐린 분비능을 증가시키며, 백색지방세포는 여분의 에너지 저장을 위해 지방세포의 크기증가 및 지방세포 분화, 더 나아가 염증반응을 야기하기도 한다. 그러나 지속된 비만으로 인한 과도한 변화 및 조절 이상은 다수의 대사질환의 원인이 되기도 한다. 여러 연구들을 통해 SREBP1c라는 유전자가 다양한 대사기관들의 기능에 관여할 수 있음이 보고되었으나, 최근까지 비만 시 발생하는 췌장 및 지방조직에서 SREBP1c의 역할에 대한 연구는 여전히 부족하다.
본 연구는 비만 시 발생하는 췌장 베타세포의 보상작용과 지방세포의 노화반응에 있어 SREBP1c가 중요한 역할을 할 수 있음을 규명하였다. 먼저, 췌장의 베타세포에서 SREBP1c는 높아진 인슐린 요구량에 반응하여 베타세포의 증식 및 인슐린 분비능 향상에 기여한다는 것을 밝혔다. 이 과정에서 SREBP1c는 새로운 표적유전자인 PAX4 발현조절을 통해 세포주기 조절 및 인슐린 분비능 관련 유전자들의 발현 변화를 매개하였다. 또한, SREBP1c 과발현 췌장 섬세포 이식은 당뇨병 유도 생쥐모델의 인슐린 생산을 회복시켜, 혈당을 낮추는 효과를 관찰하였다. 이를 통해 SREBP1c가 비만에 대한 췌장베타세포의 보상작용을 매개하는 주요인자로 작용함을 제안하였다.
다음으로 SREBP1c가 비만 시 관찰하는 지방세포의 노화반응에 관여할 수 있음을 규명하였다. 지방세포는 DNA 손상 복구능력이 상대적으로 낮으며, 비만으로 인한 스트레스에 의해 유전적 불안정성이 높아질 뿐 아니라, 노화가 쉽게 유발되는 세포임을 관찰하였다. 지방세포 내 SREBP1c는 지방대사 조절과는 별개로, DNA 복구효소인 PARP1의 활성조절을 통해 지방세포의 DNA 복구과정에 참여함을 새로이 밝혀냈다. 반대로, SREBP1c 결핍생쥐모델은 비만 시 백색지방조직 내 노화지방세포의 과잉 축적을 보이며, 노화지방세포 매개 염증반응과 전신적 인슐린 민감도 저하를 보였다. 이를 통해 SREBP1c가 지방세포의 유전적 안정성 및 세포노화현상을 매개하는 중요한 인자이며, SREBP1c 기능저하 또는 결손은 비만으로 인한 인슐린 저항성의 원인이 될 가능성을 암시한다.
종합적으로, 본 연구를 통해 SREBP1c는 비만 시 췌장과 백색지방조직의 기능변화를 매개하는 주요한 인자 중 하나임을 제안한다. 더 나아가, 새로이 규명한 SREBP1c의 기능 및 작용기전은 당뇨를 포함한 대사질환의 치료제 개발에 핵심지식을 제공할 것으로 기대한다.		-
dc.description.tableofcontentsABSTRACT................................................................................................................i
TABLE OF CONTENTS.........................................................................................iii
LIST OF FIGURES....................................................................................................v
BACKGROUNDS....................................................................................................1
1. Obesity and metabolic disorders....................................................................1
1) Pancreatic islets and obesity…………..……………..............................1
2) Adipose tissue and obesity……………………….....................2
2.Sterol Regulatory Element Binding Proteins (SREBPs)……………………..5
1) Lipid metabolism and SREBP1c...........................................................5
2) Patho-physiological function of SREBP1c..............................................8
3. PURPOSE OF THE STUDY……................................................................10
RESULTS...............................................................................................................12
Part One: SREBP1c-PAX4 Axis Mediates Pancreatic β Cell Compensatory Responses Upon Metabolic Stress .....................................................12
1. Abstract
2. Introduction
3. Material and methods
4. Results
5. Discussion
Part Two: Role of SREBP1c in maintaining genomic integrity of adipocytes against obesity-associated cellular senescence.................................54
1. Abstract
2. Introduction
3. Material and methods
4. Results
5. Discussion
CONCLUSION and PERSPECTIVES..................................................................99
ABSTRACT IN KOREAN....................................................................................102
REFERENCES......................................................................................................105





 
LIST OF FIGURES

Figure 1. Compensatory response of pancreatic β cells in obesity......................................4
Figure 2. Characteristics of senescent cell……..........................................................6
Figure 3. Patho-physiological roles of SREBP1c.......................................................9
Figure 4. SREBP1c is upregulated in pancreatic islets of obese animals.................21
Figure 5. SREBP1c is upregulated in pancreatic islets of diabetic animals.............22
Figure 6. Other SREBP1 isoform expression was not altered in pancreatic islets of diabetic animals ……………………………………………………......23
Figure 7. SREBP1c WT mice and SREBP1c KO mice showed similar body weight gain with NCD and HFD feeding………………………………………..25
Figure 8. SREBP1c KO mice exhibited decreased serum insulin and increased blood glucose with NCD and HFD feeding........................................................26
Figure 9. SREBP1c KO mice exhibited glucose intolerance with NCD and HFD feeding…………………………………………...……………………...27
Figure 10. SREBP1c KO mice showed no difference in development or distribution of insulin-positive cells.............................................................................28
Figure 11. SREBP1c KO mice exhibited smaller area of insulin-positive β cell area……………………………………………………………………...30
Figure 12. SREBP1c KO mice exhibited decreased total insulin contents in pancreas....................................................................................................31
Figure 13. SREBP1c KO mice exhibited decreased number of proliferating β cells upon HFD feeding....................................................................................32
Figure 14. SREBP1c KO mice exhibited decreased expression of cell cycle related genes.........................................................................................................33
Figure 15. SREBP1c KO mice exhibited increased number of apoptotic β cells upon HFD feeding.............................................................................................34
Figure 16. SREBP1c overexpression upregulated Pax4 mRNA in pancreatic β cell lines...........................................................................................................35
Figure 17. PAX4 level was decreased in pancreatic islets of SREBP1c KO mice…37
Figure 18. SREBP1c stimulated PAX4 promoter activity as a novel target gene.....38
Figure 19. PAX4 expression showed positive correlation with pancreatic β cell proliferation..............................................................................................39
Figure 20. SREBP1c-PAX4 axis regulated expression of cell cycle genes and insulin secretion-related genes in pancreatic β cells……………………………..40
Figure 21. SREBP1c-PAX4 axis regulated proliferation and insulin secretion capacity of pancreatic β cells....................................................................41
Figure 22. SREBP1c and PAX4 overexpression rescued expression of cell cycle genes and insulin secretion-related genes in pancreatic islets of SREBP1c KO mice....................................................................................................43
Figure 23. SREBP1c-PAX4 axis regulated expression of cell cycle genes and insulin secretion capacity of pancreatic islets.......................................................44
Figure 24. SREBP1c overexpression increased serum insulin level........................45
Figure 25. SREBP1c deficient islets exhibited low capacity of insulin secretion....46
Figure 26. SREBP1c deficiency increased glucagon expression in pancreatic islets..........................................................................................................48
Figure 27. Graphical summary 1..............................................................................53
Figure 28. White adipose tissues are susceptible to cellular senescence in obesity...63
Figure 29. White adipose tissues are also susceptible to cellular senescence in aging.........................................................................................................64
Figure 30. Adipocytes are more prone to be senescent upon obesity than SVC…....65
Figure 31. Accumulated DNA damage in eWAT upon HFD feeding......................67
Figure 32. Defected DNA repair activity in adipocytes............................................68
Figure 33. Adipocytes were susceptible cell type upon DNA damage induction......69
Figure 34. Strategy for finding candidate genes for adipocyte senescence..............70
Figure 35. SREBP1c expression was downregulated in adipocytes upon various stress including HFD feeding....................................................................72
Figure 36. SREBP1c deficiency lowered DNA repair capacity in adipocytes..........73
Figure 37. Lipogenesis is independent to genome instability-derived from SREBP1c deficient adipocytes..................................................................................74
Figure 38. Physical interaction between SREBP1c and PARP1..............................76
Figure 39. SREBP1c upregulated PARP1 activity....................................................77
Figure 40. SREBP1c deficiency lowered PARP1's recruitment ability to damaged region and affinity with damaged DNA....................................................79
Figure 41. SREBP1c-PARP1 axis regulates adipocyte senescence through DNA repair capacity...........................................................................................80
Figure 42. Body weight and food intake of SREBP1c WT & KO mice upon HFD..........................................................................................................81
Figure 43. SREBP1c deficiency aggravated cellular senescence in adipocytes of eWAT upon HFD.......................................................................................82
Figure 44. SREBP1c deficient eWAT exhibited DNA damage accumulation upon HFD due to low PARP1 activity...............................................................84
Figure 45. Senescent adipocytes from SREBP1c deficiency exhibited high chemotactic ability to immune cells through cytokines...........................85
Figure 46. SREBP1c deficient mice exhibited glucose intolerance and insulin resistance upon HFD................................................................................86
Figure 47. SREBP1c deficient eWAT exhibited pro-inflammatory characteristics upon HFD.................................................................................................88
Figure 48. Removal of phagocyte rescues insulin resistance of SREBP1c deficient mice..........................................................................................................89
Figure 49. Dasatinib + Quercetin effectively removes senescent adipocytes..........91
Figure 50. Dasatinib + Quercetin treatment during HFD feeding............................92
Figure 51. Dasatinib + Quercetin improves glucose tolerance and insulin sensitivity of SREBP1c deficient mice......................................................................93
Figure 52. Dasatinib + Quercetin improves cellular senescence and inflammatory response in eWAT.....................................................................................94
Figure 53. Graphical summary 2..............................................................................98		-
dc.format.extentviii, 115-
dc.language.isoeng-
dc.publisher서울대학교 대학원-
dc.subjectSREBP1c-
dc.subjectPAX4-
dc.subjectPARP1-
dc.subject비만-
dc.subject대사질환-
dc.subject당대사 이상-
dc.subject인슐린 저항성-
dc.subject췌장 베타세포-
dc.subject베타세포 보상작용-
dc.subject지방조직 염증반응-
dc.subject세포노화-
dc.subjectObesity-
dc.subjectMetabolic disorders-
dc.subjectInsulin resistance-
dc.subjectCompensatory responses of pancreatic β cells-
dc.subjectAdipocyte senescence-
dc.subject.ddc570-
dc.titleNovel Roles of SREBP1c in the Regulation of Compensatory Responses of Pancreatic β cells and Cellular Senescence in Adipocytes-
dc.title.alternative췌장 베타세포 보상작용 및 지방세포 노화현상을 매개하는 SREBP1c의 역할 연구-
dc.typeThesis-
dc.typeDissertation-
dc.contributor.AlternativeAuthorGung Lee-
dc.contributor.department자연과학대학 생명과학부-
dc.description.degreeDoctor-
dc.date.awarded2021-02-
dc.identifier.uciI804:11032-000000165567-
dc.identifier.holdings000000000044▲000000000050▲000000165567▲-
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