• 생명과학회지
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• 제31권9호
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• pp.796-805
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• 2021

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.

• BMB Reports
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• 제51권1호
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• pp.33-38
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• 2018

Sterol regulatory element-binding protein-1c (SREBP1c) plays an important role in triglyceride (TG) homeostasis. Although our previous study showed that hepatitis C virus core-binding protein 6 (HCBP6) regulates SREBP1c expression to maintain intracellular TG homeostasis, the mechanism underlying this regulation is unclear. In the present study, we found that HCBP6 increased intracellular TG levels by upregulating SREBP1c expression. HCBP6 increased SREBP1c transcription by directly binding to the SREBP1c promoter (at the -139- to +359-bp region). Moreover, we observed that HCBP6 interacted with $C/EBP{\beta}-binding$ site in the SREBP1c promoter both in vitro and in vivo. These results indicate that HCBP6 upregulates human SREBP1c expression by binding to the $C/EBP{\beta}-binding$ site in the SREBP1c promoter.

• Animal cells and systems
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• 제8권1호
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• pp.49-55
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• 2004

In vertebrates, multisubunit cofactors regulate gene expression through interacting with cell-type- and gene-specific DNA-binding proteins in a chromatin-selective manner. ADD1/SREBP1c regulates fatty acid metabolism and insulin-dependent gene expression through binding to SRE and E-box motif with dual DNA binding specificity. Although its transcriptional and post-translational regulation has been extensively studied, its regulation by interacting proteins is not well understood. To identify cellular proteins that associate with nuclear form of ADD1/SEBP1c, we employed the GST pull-down system with Hela cell nuclei extract. In this study, we demonstrated that Ku proteins interact specifically with ADD1/SREP1c protein. GST pull-down combined with peptide sequencing analysis revealed that Ku80 binds to ADD1/SREBP1c in vitro. Additionally, western blot analysis showed that Ku70, a heterodimerizing partner of Ku80, also associates with ADD1/SREBP1c. Furthermore, co-transfection of Ku70/Ku80 with ADD1/SREBP1c enhanced the transcriptional activity of ADD1/SREBP1c. Taken together, these results suggest that the Ku proteins might be involved in the lipogenic and/or adipogenic gene expression through interacting with ADD1/SREBP1c.

• 생명과학회지
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• 제25권3호
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• pp.317-322
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• 2015

알코올에 의한 지방간(지방변성증)은 에탄올 대사에 의해 감소되는 당량의 과도한 발생에 의해 유발된다. 일반적으로 만성적인 에탄올 투여는 간 지질의 합성을 증가시키는 sterol regulatory element-binding protein 1c (SREBP-1c)를 조절함으로써 지방변성증을 유발시킨다. SPEBP-1c에서 에탄올의 영향은 간에서의 지방대사를 조절하는 NAD⁺ 의존적 단백질 탈아세틸화효소인 mammalian sirtuin-1 (SIRT-1)에 의해 조정된다. 홍삼은 항당뇨와 항비만 효과를 위해 아시아에서 광범위하게 사용되는 한약재이다. 홍삼의 약리학적 치료학적인 효과는 진세노사이드와 같은 생물활성 성분에 의해 주로 일어난다. 따라서 우리는 마우스 간세포주인 AML-12 세포에서 SREBP-1과 SIRT-1에대한 한국홍삼 추출물의 조절효과를 평가하였다. 알코올과 홍삼추출물(0-1,000 μg/ml)을 AML-12 세포주에 처리하고, 지방소립을 Oil red O 염색법으로 확인하고, western blots을 사용해 SIRT-1과 SREBP-1의 발현을 확인하였다. 에탄올을 처리한 세포에서 홍삼추출물은 SIRT-1과 SREBP-1c의 발현을 회복시켰다. 또한 에탄올이 처리된 세포에서 홍삼추출물과 진세노사이드 Rb₂와 Rd가 SREBP-1을 유의적으로 감소시키는 것으로 확인 되었다. 결과적으로 홍삼과 활성 진세노사이드 성분인 Rb₂와 Rd가 SIRT-1과 간 지질대사를 변화시키는 SREBP-1c의 아세틸화의 조절을 통해 알코올에 의한 간지방변성을 억제하는 것을 확인하였다.

• 생명과학회지
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• 제28권10호
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• pp.1233-1243
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• 2018

SREBPs는 지질의 항상성 및 대사를 조절하는 전사 인자이다. 이들은 내인성 콜레스테롤, 지방산(FA), 트리아실글리세롤(TG) 및 인지질 합성에 필요한 효소의 발현을 정밀하게 조절한다. 3종류의 SREBP 단백질은 2개의 다른 유전자에 의해 암호화 된다. SREBP1 유전자는 SREBP-1a와 SREBP-1c를 만든다. 이는 RNA의 alternative splicing에 의한 대체 프로모터의 이용으로부터 유도된다. SREBP-2는 별도의 유전자에서 유래한다. 또한, SREBPs는 ER 스트레스, 염증, 자가포식 및 세포사멸과 같은 수많은 병인과정에 관여하며, 비만, 이상 지질혈증, 당뇨병 및 비알콜성 지방간 질환 등을 유발하는 것으로 알려져 있다. 유전체의 분석은 SREBPs가 생물학적 신호 전달, 세포 신진 대사, 및 성장을 조절하는 중요한 연결고리임을 보여 주었다. 이 과정에서 SREBP는 PI3K-Akt-mTOR 경로를 통해 활성화 된다고 알려져 있다. 하지만 정확한 분자 메커니즘은 좀더 밝혀져야 한다. 이 리뷰에서는 세포, 기관 및 생물개체 수준의 생리학 및 병태 생리학 영역에서 SREBP의 역할에 대한 포괄적인 이해를 넓혀 줄 것이다.

• Journal of Ginseng Research
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• 제29권4호
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• pp.159-166
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• 2005

Ginsenosides, a group of Panax ginseng saponins, exert the lowering effects of plasma cholesterol levels in animals. We had reported earlier that ginsenoside Rb2 upregulate low-density lipoprotein receptor (LDLR) expression via a mechanism that is dependent of the activation of sterol response element binding protein 2 (SREBP-2) expression. This study was conducted to determine the effects of ginsenoside Rb2 on the expression of the hepatic LDLR expression at cellular levels using HepG2 cells, and to evaluate whether the sterol response element binding protein 1 (SREBP-l) was involved in the regulation of LDLR expression. Incubation of HepG2 cells in serum-free medium supplemented with cholesterol $(10{\mu}g/ml)$ for 8 hours decreased the mRNAs of LDLR mRNA by $12\%$ and SREBP-l mRNA by $35\%$. Ginsenoside Rb2 antagonized the repressive effects of cholesterol and increased both LDLR and SREBP-l mRNA expression to 1.5- and 2-fold, respectively. Furthermore, Western blot and confocal microscopic analyses with SREBP-l polyclonal antibody revealed that ginsenoside Rb2 enhanced the maturation of the SREBP-1 from the inactive precursor form in ER membrane to the active transcription factor form in nucleus. These results suggest that ginsenoside Rb2 upregulates LDLR expression via a mechanism that is dependent of the activation of not only SREBP-2 expression, but also SREBP-1 expression and maturation, and also indicate that the pharmacological value of ginsenoside Rb2 may be distinguished from that of lovastatin which is reported that it upregulate LDLR through SREBP-2 only, not through SREBP-1.

• Toxicological Research
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• 제33권3호
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• pp.219-224
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• 2017

Lipin1 was identified as a phosphatidate phosphatase enzyme, and it plays a key role in lipid metabolism. Since free radicals contribute to metabolic diseases in the liver, this study investigated the effects of free radicals on the regulation of Lipin1 expression in Huh7 and AML12 cells. Hydrogen peroxide induced mRNA and protein expression of Lipin1 in Huh7 cells, which was assayed by quantitative RT-PCR and immunoblotting, respectively. Induction of Lipin1 by hydrogen peroxide was confirmed in AML12 cells. Hydrogen peroxide treatment significantly increased expression of sterol regulatory element-binding protein (SREBP)-2, but not SREBP-1. Moreover, nuclear translocation of SREBP-2 was detected after hydrogen peroxide treatment. Hydrogen peroxide-induced Lipin1 or SREBP-2 expression was significantly reduced by N-acetyl-$\small{L}$-cysteine treatment, indicating that reactive oxygen species (ROS) were implicated in Lipin1 expression. Next, we investigated whether the hypoxic environments that cause endogenous ROS production in mitochondria in metabolic diseases affect the expression of Lipin1. Exposure to hypoxia also increased Lipin1 expression. In contrast, pretreatment with antioxidants attenuated hypoxia-induced Lipin1 expression. Collectively, our results show that ROS activate SREBP-2, which induces Lipin1 expression.

• BMB Reports
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• 제40권4호
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• pp.525-531
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• 2007

As a $\beta_2$-adrenergic agonist, clenbuterol decreases body fat, but the molecular mechanism underlying this process is unclear. In the present study, we treated 293T and L-02 cells with clenbuterol and found that clenbuterol downregulates SREBP-1c expression and upregulates CREB1 expression. Considering SREBP-1c has the function of regulating the transcription of several lipogenic enzymes, we considered that the downregulation of SREBP-1c is responsible for body fat reduction by clenbuterol. Many previous studies have found that clenbuterol markedly increases intracellular cAMP levels, therefore, we also investigated whether CREB1 is involved in this process. The data from our experiments indicate that CREB1 overexpression inhibits SREBP-1c transcription, and that this action is antagonized by CREB2, a competitive inhibitor of CREB1. Furthermore, since PPARs are able to repress SREBP-1c transcription, we investigated whether clenbuterol and CREB1 function via a pathway involving PPAR activation. However, our results showed that clenbuterol or CREB1 overexpression suppressed PPARs transcription in 293T and L-02 cells, which suggested that they impair SREBP-1c expression in other ways.

• 대한한의학방제학회지
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• 제30권3호
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• pp.137-143
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• 2022

Objectives : Brain-Liver axis is an important target of the chronic human diseases. Hepatic steatosis is one of the most famous disorders in the chronic diseases. This study investigated the moderating effect of beneficial herbs on the fat accumulation, which is mediated by the LXR alpha-SREBP-1c signaling pathway. Methods : In order to confirm the SREBP-1c inhibitory effect, we performed immonoblotting ananlysis using HepG2 cells and Huh 7 cells treated by T0901317, the ligand of LXRα. Results : Forsythiae suspensa water extract (FSE) was not cytotoxicity in cell lines. FSE inhibited SREBP-1c protein expression in HepG2 and Huh7 cells induced by T0901317. In addition, FSE increased the phosphorylation of LKB1, which is associated with LXR-related pathway in HepG2 and Huh 7 cells. Conclusions : These results showed that FSE activated LKB1 to suppress SREBP-1c, which protects the cells against oxidative stress.

• 한국발생생물학회지:발생과생식
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• 제26권2호
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• pp.49-58
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• 2022

The differentiation and development of preadipocyte into mature adipocyte are regulated by transcription factors, such as CCAAT enhancer binding protein (Cebp) gene family and sterol regulatory element binding transcription factor 1 (Srebp1). Steroid hormones give influences on the development and function of adipocyte. The present research examined expression patterns of CCAAT enhancer binding protein alpha (Cebpa), CCAAT enhancer binding protein beta (Cebpb), CCAAT enhancer binding protein gamma (Cebpg), sterol regulatory element binding transcription factor 1 (Srebp1), androgen receptor (Ar), and estrogen receptors (Esr) among different epididymal fat parts during postnatal period by quantitative real-time polymerase chain reaction. In the distal epididymal fat, expression of Cebpa, Cebpb, Cebpg, Srebp1, Ar, and Esr2 was increased until 12 months of age, while expression of Esr1 was decreased at 5 months of age and was not detectable after 8 months of age. In the proximal epididymal fat, transcript levels of Cebps and Srebp1 were increased at 8 months of age, followed by decreases of Cebpb and Cebpg transcript levels at 12 months of age. An additional increase of Srebp1 expression was observed at 12 months of age. Expression of Ar and Esr2 were increased until 8 months of age, followed by a drop of Ar expression level at 12 months of age. Expression pattern of Esr1 was similar to that in the distal epididymal fat. In the tail epididymal fat, expression of Cebpa, Cebpg, Srebp1, Ar, and Esr2 was increased with age. Esr1 was not detectable at all. The highest level of Cebpb was observed at 8 months of age. These data suggest the possibility of developmental and functional differentiation among the epididymal fat parts.