[논문]지방산 산화 장애 제어를 통한 SREBP-1c 결핍의 소포체 스트레스 유발 비알콜성지방간 보호작용

이영승; 티모씨 에프 오스본; 서영교; 전태일

doi:10.5352/jls.2021.31.9.796

지방산 산화 장애 제어를 통한 SREBP-1c 결핍의 소포체 스트레스 유발 비알콜성지방간 보호작용
SREBP-1c Ablation Protects Against ER Stress-induced Hepatic Steatosis by Preventing Impaired Fatty Acid Oxidation 원문보기

생명과학회지 = Journal of life science, v.31 no.9, 2021년, pp.796 - 805

이영승 (전남대학교 농업생명과학대학 동물자원학부) , 티모씨 에프 오스본 (존스 홉킨스 의과대학) , 서영교 (한국생명공학연구원 노화제어전문연구단) , 전태일 (전남대학교 농업생명과학대학 동물자원학부)

초록
AI-Helper

간 소포체(ER) 스트레스는 비알콜성지방간과 인슐린 저항성의 발달에 기여하고, unfolded protein response(UPR)의 구성요소는 지질 대사를 조절한다. 최근 연구에 따르면 ER 스트레스와 비정상적인 세포 지질 대사 사이의 연관성이 보고되었으며, 이 과정에서 지질 대사의 중심 조절자인 sterol regulatory element binding proteins(SREBPs)의 관련성이 확인되었다. 그러나 ER 스트레스 동안 지질 대사를 조절하는 SREBP의 정확한 역할과 비알콜성지방간에 대한 기여는 아직 밝혀지지 않았다. 본 연구에서 SREBP-1c 결핍은 UPR, 염증 및 지방산 산화 조절을 통해 ER 스트레스에 의해 유도된 비알콜성지방간으로부터 생쥐를 보호한다는 것을 보여준다. SREBP-1c는 inositol requiring kinase 1α (IRE1α) 발현을 직접적으로 조절하고 ER 스트레스에 의해 유도된 tumor necrosis factor-α의 활성화를 매개하여 peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α)의 감소와 그에 따른 지방산 산화의 장애를 유발한다. 그러나, SREBP-1c의 유전적 결핍은 이러한 현상을 보호하여 간 염증과 지방 축적을 완화시킨다. SREBP-1c 결핍이 ER 스트레스에 의해 유도된 염증 신호를 방지하는 메커니즘은 아직 밝혀지지 않았지만, SREBP-1c가 결핍된 Kupffer 세포에서 IRE1α 신호의 변화가 염증 신호에 관여할 수 있을 것으로 생각된다. 본 연구결과는 SREBP-1c가 ER 스트레스에 의해 유도된 비알콜성지방간에서 UPR 및 염증의 조절에 중요한 역할을 함을 시사한다.

Abstract ▼ AI-Helper

Hepatic endoplasmic reticulum (ER) stress contributes to the development of steatosis and insulin resistance. The components of unfolded protein response (UPR) regulate lipid metabolism. Recent studies have reported an association between ER stress and aberrant cellular lipid control; moreover, research has confirmed the involvement of sterol regulatory element-binding proteins (SREBPs)-the central regulators of lipid metabolism-in the process. However, the exact role of SREBPs in controlling lipid metabolism during ER stress and its contribution to fatty liver disease remain unknown. Here, we show that SREBP-1c deficiency protects against ER stress-induced hepatic steatosis in mice by regulating UPR, inflammation, and fatty acid oxidation. SREBP-1c directly regulated inositol-requiring kinase 1α (IRE1α) expression and mediated ER stress-induced tumor necrosis factor-α activation, leading to a reduction in expression of peroxisome proliferator-activated receptor γ coactivator 1-α and subsequent impairment of fatty acid oxidation. However, the genetic ablation of SREBP-1c prevented these events, alleviating hepatic inflammation and steatosis. Although the mechanism by which SREBP-1c deficiency prevents ER stress-induced inflammatory signaling remains to be elucidated, alteration of the IRE1α signal in SREBP-1c-depleted Kupffer cells might be involved in the signaling. Overall, the results suggest that SREBP-1c plays a crucial role in the regulation of UPR and inflammation in ER stress-induced hepatic steatosis.

주제어

표/그림 (4)

표 Table 1. Primer sequences used in this study
그림 Fig. 1. SREBP-1c activates IRE1α transcription. (A) Sequence reads from SREBP-1c ChIP-Seq experiments were mapped onto the mouse genome in the University of California Santa Cruz (UCSC) Genome Browser. The SREBP-1c binding site at the Ire1α gene locus is pointed by arrows. (B) ChIP assay for SREBP-1 (BP1) binding in liver chromatin from fasted (F) or refed (RF) mice. Acetyl-CoA carboxylase 2 (Acc2) was used as a positive control. (C) Relative mRNA levels of Ire1α and Chop in the liver of fed, fasted, or refed mice. (D) AML12 cells were treated with 0.5 mM palmitic acid (PA)-BSA conjugates at an indicated time. Immunoblots for precursor (p) and nuclear (n) SREBP-1 and ER stress markers (E and F). Ire1α mRNA levels in HeLa cells infected with recombinant adenovirus expressing SREBP-1c (Ad-1c) or transfected with siRNA targeting SREBP-1c (BP1i), followed by incubation with 1 μM thapsigargin (Tg). (G) Primary hepatocytes isolated from WT and 1cKO mice were treated with 10 μg/ml tunicamycin (Tu) at an indicated time. IRE1α was analyzed by immunoblotting. Data are mean ± SEM. *p<0.05 versus F BP1 (B) or Fed (C) by one-way ANOVA; * p<0.05 by Student’s t-test (E and F).
그림 Fig. 2. SREBP-1c deficiency protects against ER stress-induced hepatic steatosis. (A) Relative mRNA expression of ER stress markers in the liver of WT and 1cKO mice 72 hr after treatment with 1 mg/kg body weight of Tu. (B) Xbp1 splicing was analyzed by RT-PCR. (C) Immunoblots for liver ER stress markers. (D) H&E staining of the liver of mice. Scale bars, 100 μm. (E) Liver triglyceride and total cholesterol levels. (F) Hepatic mRNA levels of genes encoding SREBP-1c and lipogenic enzymes. Data are mean ± SEM. # p<0.05 versus WT-Vehicle (Veh) and * p<0.05 versus WT-Tu by one-way ANOVA (A); * p<0.05 versus WT by two-way ANOVA (E).
그림 Fig. 3. SREBP-1c deficiency suppresses ER stress-induced inflammation and fatty acid oxidation dysregulation. (A) Relative mRNA expression of genes involved in fatty acid oxidation in the liver of WT and 1cKO mice 72 hr after Tu injection. (B) Rate of fatty acid oxidation. (C) Immunohistochemistry for a macrophage marker F4/80 (green). Scale bars, 100 μm. The number of F4/80-positive cells was counted using Image J. (D) Relative mRNA levels of TNF-α and IL-1β. (E) mRNA levels of Pgc-1α from WT and 1cKO primary hepatocytes treated with TNF-α in a dose-dependent manner. Data are mean ± SEM. # p<0.05 versus WT-Veh and * p<0.05 versus WT-Tu by one-way ANOVA (A, B, and C); * p<0.05 versus WT by two-way ANOVA (D).

AI 본문요약
AI-Helper

데이터처리

A two-tailed, unpaired Student’s t-test was used for the pairwise comparison of treatments
One-way or two-way ANOVA was used to compare three or more groups, followed by Tukey’s multiple comparison test, as shown in the figures

참고문헌 (33)

Chen, J., Fontes, G., Saxena, G., Poitout, V. and Shalev, A. 2010. Lack of TXNIP protects against mitochondria-mediated apoptosis but not against fatty acid-induced ER stress-mediated beta-cell death. Diabetes 59, 440-447.

상세보기
Chen, Y. and Brandizzi, F. 2013. IRE1: ER stress sensor and cell fate executor. Trends Cell Biol. 23, 547-555.

상세보기
Cnop, M., Foufelle, F. and Velloso, L. A. 2012. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol. Med. 18, 59-68.

상세보기
Djouadi, F., Bonnefont, J. P., Munnich, A. and Bastin, J. 2003. Characterization of fatty acid oxidation in human muscle mitochondria and myoblasts. Mol. Genet. Metab. 78, 112-118.

상세보기
Horton, J. D., Bashmakov, Y., Shimomura, I. and Shimano, H. 1998. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc. Natl. Acad. Sci. USA. 95, 5987-5992.

상세보기
Hu, P., Han, Z., Couvillon, A. D., Kaufman, R. J. and Exton, J. H. 2006. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol. Cell. Biol. 26, 3071-3084.

상세보기
Huang, W., Metlakunta, A., Dedousis, N., Zhang, P., Sipula, I., Dube, J. J., Scott, D. K. and O'Doherty, R. M. 2010. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59, 347-357.

상세보기
Inoue, N., Shimano, H., Nakakuki, M., Matsuzaka, T., Nakagawa, Y., Yamamoto, T., Sato, R., Takahashi, A., Sone, H., Yahagi, N., Suzuki, H., Toyoshima, H. and Yamada, N. 2005. Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor. Mol. Cell. Biol. 25, 8938-8947.

상세보기
Jeon, T. I., Esquejo, R. M., Roqueta-Rivera, M., Phelan, P. E., Moon, Y. A., Govindarajan, S. S., Esau, C. C. and Osborne, T. F. 2013. An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis. Cell Metab. 18, 51-61.

상세보기
Jeon, T. I. and Osborne, T. F. 2012. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol. Metab. 23, 65-72.

상세보기
Jo, H., Choe, S. S., Shin, K. C., Jang, H., Lee, J. H., Seong, J. K., Back, S. H. and Kim, J. B. 2013. Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor. Hepatology 57, 1366-1377.

상세보기
Kammoun, H. L., Chabanon, H., Hainault, I., Luquet, S., Magnan, C., Koike, T., Ferre, P. and Foufelle, F. 2009. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest. 119, 1201-1215.

상세보기
Lebeaupin, C., Vallee, D., Hazari, Y., Hetz, C., Chevet, E. and Bailly-Maitre, B. 2018. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927-947.

상세보기
Lee, A. H., Scapa, E. F., Cohen, D. E. and Glimcher, L. H. 2008. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320, 1492-1496.

상세보기
Li, H., Min, Q., Ouyang, C., Lee, J., He, C., Zou, M. H. and Xie, Z. 2014. AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim. Biophys. Acta 1842, 1844-1854.

상세보기
Lin, J. H., Li, H., Yasumura, D., Cohen, H. R., Zhang, C., Panning, B., Shokat, K. M., Lavail, M. M. and Walter, P. 2007. IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944-949.

상세보기
Logette, E., Le Jossic-Corcos, C., Masson, D., Solier, S., Sequeira-Legrand, A., Dugail, I., Lemaire-Ewing, S., Desoche, L., Solary, E. and Corcos, L. 2005. Caspase-2, a novel lipid sensor under the control of sterol regulatory element binding protein 2. Mol. Cell. Biol. 25, 9621-9631.

상세보기
Martinon, F., Chen, X., Lee, A. H. and Glimcher, L. H. 2010. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411-418.

상세보기
Ning, J., Hong, T., Ward, A., Pi, J., Liu, Z., Liu, H. Y. and Cao, W. 2011. Constitutive role for IRE1alpha-XBP1 signaling pathway in the insulin-mediated hepatic lipogenic program. Endocrinology 152, 2247-2255.

상세보기
Osborne, T. F. 2000. Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J. Biol. Chem. 275, 32379-32382.

상세보기
Osborne, T. F. and Espenshade, P. J. 2009. Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been. Genes Dev. 23, 2578-2591.

상세보기
Palomer, X., Alvarez-Guardia, D., Rodriguez-Calvo, R., Coll, T., Laguna, J. C., Davidson, M. M., Chan, T. O., Feldman, A. M. and Vazquez-Carrera, M. 2009. TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc. Res. 81, 703-712.

상세보기
Postic, C. and Girard, J. 2008. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 118, 829-838.

상세보기
Rutkowski, D. T., Wu, J., Back, S. H., Callaghan, M. U., Ferris, S. P., Iqbal, J., Clark, R., Miao, H., Hassler, J. R., Fornek, J., Katze, M. G., Hussain, M. M., Song, B., Swathirajan, J., Wang, J., Yau, G. D. and Kaufman, R. J. 2008. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev. Cell 15, 829-840.

상세보기
Schroder, M. and Kaufman, R. J. 2005. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739-789.

상세보기
Seo, Y. K., Chong, H. K., Infante, A. M., Im, S. S., Xie, X. and Osborne, T. F. 2009. Genome-wide analysis of SREBP-1 binding in mouse liver chromatin reveals a preference for promoter proximal binding to a new motif. Proc. Natl. Acad. Sci. USA. 106, 13765-13769.

상세보기
Shen, J., Chen, X., Hendershot, L. and Prywes, R. 2002. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3, 99-111.

상세보기
Truong, X. T., Nguyen, T. T. P., Kang, M. J., Jung, C. H., Lee, S., Moon, C., Moon, J. H. and Jeon, T. I. 2019. Pear extract and malaxinic acid reverse obesity, adipose tissue inflammation, and hepatosteatosis in mice. Mol. Nutr. Food Res. 63, e1801347.

상세보기
Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H. P. and Ron, D. 2000. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664-666.

상세보기
Werstuck, G. H., Lentz, S. R., Dayal, S., Hossain, G. S., Sood, S. K., Shi, Y. Y., Zhou, J., Maeda, N., Krisans, S. K., Malinow, M. R. and Austin, R. C. 2001. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J. Clin. Invest. 107, 1263-1273.

상세보기
Yang, Q., Kim, Y. S., Lin, Y., Lewis, J., Neckers, L. and Liu, Z. G. 2006. Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep. 7, 622-627.

상세보기
Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S. and Goldstein, J. L. 2000. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355-1364.

상세보기
Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L. and Wymer, M. 2016. Global epidemiology of nonalcoholic fatty liver disease-meta analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73-84.

상세보기

표제어: PCR

동의어: Packet Collision Rate

용어 설명 출처 목록 (6)

용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

내보내기 구분	파일저장 인쇄 메일전송
구성항목	기본정보 상세정보 관리번호, 논문명, 저널/프로시딩명, 저자 , 발행년, 권, 호, 시작페이지, 끝페이지, 발행기관 관리번호, 논문명, 대등논문명, 저자 , 저널/프로시딩명, 발행기관, 발행년, 발행언어, 권, 호, 시작페이지, 끝페이지, ISBN, ISSN, 주제분야, 키워드, 초록(한글), 초록(영문), 저자(소속기관)
저장형식	Text(ASCII format) Excel format RefWorks Direct Export RIS format (for Reference Manager, ProCite, EndNote), Scholar's Aids, Mendeley
메일정보	받는사람 (필수) @ 보내는사람 (선택) @ 제목 내용 KISTI 검색결과 이메일 서비스
안내	총 건의 자료가 검색되었습니다. 다운받으실 자료의 인덱스를 입력하세요. (1-10,000) 검색결과의 순서대로 최대 10,000건 까지 다운로드가 가능합니다. 데이타가 많을 경우 속도가 느려질 수 있습니다.(최대 2~3분 소요) 다운로드 파일은 UTF-8 형태로 저장됩니다. 파일의 내용이 제대로 보이지 않을실 때는 웹브라우저 상단의 보기 -> 인코딩 -> 자동선택 여부를 확인하십시오. ~ Text(ASCII format) Excel format

연합인증