EP1888084A1 - Pharmazeutische zusammensetzung zur hemmung der lipogenese mit einem regulator der prp19-expression - Google Patents

Pharmazeutische zusammensetzung zur hemmung der lipogenese mit einem regulator der prp19-expression

Info

Publication number
EP1888084A1
EP1888084A1 EP06747421A EP06747421A EP1888084A1 EP 1888084 A1 EP1888084 A1 EP 1888084A1 EP 06747421 A EP06747421 A EP 06747421A EP 06747421 A EP06747421 A EP 06747421A EP 1888084 A1 EP1888084 A1 EP 1888084A1
Authority
EP
European Patent Office
Prior art keywords
prp
expression
protein
gene
regulator
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06747421A
Other languages
English (en)
French (fr)
Inventor
Si-Young Cho
Eui-Seok Hamabimaeul Dongbu Centreville Apt. Shin
Pil-Joon Park
Dong-Wook Shin
Hui-Kyoung Geumhwamaeul Jugong Apt. Chang
Dae-Gun Sinbanpo 12-cha Apt. 325-502 Kim
Hyoung-Ho Lee
Jeong-Ho Geumhwamaeul Jugong Apt. 401-405 Lee
Tae-Ryong Lee
Ih-Seop Chang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amorepacific Corp
Original Assignee
Amorepacific Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amorepacific Corp filed Critical Amorepacific Corp
Publication of EP1888084A1 publication Critical patent/EP1888084A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links

Definitions

  • the present invention relates to a composition for the inhibition of lipogenesis comprising a regulator of PRP 19 (precursor RNA processing 19) protein expression as an active ingredient, a method for inhibiting lipogenesis by regulating PRP 19 protein expression, and a method for screening an inhibitor candidate of lipogenesis by analyzing PRP 19 gene or its protein expression.
  • a regulator of PRP 19 precursor RNA processing 19
  • PRP 19 (precursor RNA processing 19) protein is a 54 kDa protein containing six WD (tryptophan/aspartic acid) repeat domains, and it has been known to participate in the DNA recombination and repair.
  • PRP 19 protein is involved in the lipid metabolism or lipid droplet biogenesis.
  • Most organisms store surplus nutrition remaining after metabolism in lipid droplets of adipocytes in the form of neutral lipid, mainly triacylglycerol (TAG).
  • TAG triacylglycerol
  • the lipid droplet is a subcellular organelle composed of phospholipids and lipid droplet associated proteins, and deposits or transports TAG, diacylglycerol (DAG) and cholesteryl ester.
  • lipid metabolic diseases e.g., fatty liver, obesity, arteriosclerosis and diabetes are induced by a disorder of lipid droplet biogenesis, and especially, diabetes is caused by the abnormal accumulation of neutral lipids, which results from lipid droplet growing more than twice in size.
  • the lipid droplet associated proteins can be classified according to the cell type, differentiation stage, and deposition or transportation mode.
  • the representative examples thereof include apolipoprotein B which forms part of very-low density lipoprotein (VLDL), adipocyte differentiation-related protein (ADRP) which surrounds fatty clods of adipocytes, and perilipin. Most of such proteins are expressed in adipocyte-specific manner, and play an important role in carrying TAG to lipid droplets or protecting lipid droplets from lipolysis by lipases.
  • the present inventors have therefore endeavored to develop a method for effectively inhibiting lipogenesis, and have found that: PRP 19 protein is localized within lipid droplets of adipocyte and abundantly expressed in adipose tissue- specific manner; its expression is regulated depending on adipocyte differetiation stages; and the downregulation of PRP 19 protein expression dramatically reduces lipid droplet biogenesis and intracellular neutral lipid content.
  • a pharmaceutical composition for the inhibition of lipogenesis comprising a regulator of PRP 19 protein expression as an active ingredient and a pharmaceutically acceptable earner.
  • a regulator of PRP 19 protein expression for the manufacture of a medicament for inhibiting lipogenesis in a subject in need of the lipogenesis inhibition.
  • a method for screening a viable lipogenesis inhibitor comprising the steps of treating a subject with candidate inhibitors and analyzing PRP 19 gene or RPR 19 protein expression in the subject.
  • FIG. 1 PRP 19 protein expression levels in cells harvested before, and at 2, 4 and 8 days after inducing of the differentiation of 3T3-L1, a mouse embryonic fibroblast-preadipocyte cell line, determined by western blot analyses;
  • FIG. 2 Immunofluorescence assay results for determining the intracellular localization of expressed PRP 19 protein in differentiated adipocytes
  • FIG. 3 Cleavage map of pSi-PRP19 vector expressing PRP 19 siRNA of the present invention
  • FIG. 4 Western blot analysis results showing PRP 19 protein expression levels in a cell line expressing PRP 19 siRNA and a control cell line, respectively
  • FIG. 5 Microphotographs for observing lipid droplet biogenesis in a cell line expressing RPRl 9 siRNA and a control cell line, respectively;
  • FIG. 6 High performance thin layer chromatography (HPTLC) results showing the amounts of neutral lipids in a cell line expressing PRP 19 siRNA and a control cell line, respectively;
  • FIG. 7 Western blot analysis results obtained for the protein expression of FAS, perilipin, PPAR- ⁇ , C/EBP- ⁇ , SCDl and ⁇ -actin in the cell line expressing PRP 19 siRNA and the control cell line, obtained in Example 3, respectively; and FIG. 8: Real-time quantitative RT-PCR analysis results obtained for the mRNA expression of aP2, SREBP-Ic, DGAT-I and GPAT in the cell line expressing PRP 19 siRNA and the control cell line, obtained in Example 3, respectively.
  • PRP19 siRNA is siRNA capable of mediating RNA interference (RNAi) against the PRP 19 gene expression.
  • PRP 19 protein is expressed in adipose tissue-spectific manner and abundantly localized in lipid droplets of differetiated adipocytes.
  • the pharmaceutical composition of the present invention is characterized by comprising a regulator that effectively downregulates PRP 19 protein expression as an active ingredient.
  • the regulator include antisense RNAs, interfering RNAs (iRNAs) and small interfering RNAs (siRNAs) capable of mediating RNA interference (RNAi) against PRP 19 gene expression, and expression vectors thereof, which can be used for downregulating PRP 19 protein expression at its mRNA level; transcription inhibitors of PRP 19 gene; translation inhibitors of transcribed PRP 19 mRNA; and inhibitors of PRP 19 protein localization.
  • iRNAs interfering RNAs
  • siRNAs small interfering RNAs capable of mediating RNA interference (RNAi) against PRP 19 gene expression
  • expression vectors thereof which can be used for downregulating PRP 19 protein expression at its mRNA level
  • transcription inhibitors of PRP 19 gene transcription inhibitors of PRP 19 gene
  • translation inhibitors of transcribed PRP 19 mRNA and inhibitors of PRP 19 protein localization
  • composition of the present invention may further comprise pharmaceutically acceptable carriers, excipients or additives, and preferably, the inventive composition is of the form of an injection formulation for gene therapy.
  • the inventive composition may be systemically or locally administered to a subject in need of lipogenesis inhibition.
  • a suitable single dose of the active ingredient of the inventive composition for administration to a human may be about from 0.001 ng to 1000 ⁇ g, but it should be understood that the dose should be determined in light of various relevant factors including the condition to be treated, the route of administration, the age and weight of the patient, and the severity of the patient's symptoms; and, therefore, the dosage suggested above should not be construed to limit the scope of the invention in anyway.
  • the present invention provides a method for the inhibition of lipogenesis comprising the step of regulating PRP 19 protein expression in a subject in need of lipogenesis inhibition.
  • the subject may be a mammal such as a human.
  • PRP 19 protein expression may be regulated by targeting PRP 19 gene on the chromosomal DNA though the conventional gene knock-out method; targeting PRP19 mRNA using antisense RNA, iRNA and siRNA capable of mediating RNA interference (RNAi) against PRP19 gene expression, and an expression vector which can introduce one of these RNAs into cells; suppressing the transcription of PRP 19 gene; suppressing the translation of transcribed PRP 19 mRNA; or inhibiting the intracellular localization of PRPl 9 protein.
  • RNAi RNA interference
  • the inventive method it is possible to effectively downregulate the expression of SCDl (stearyl CoA desaturase-1), which is known as the key lipogenic enzyme, as well as its down-stream triacylglycerol synthesis enzymes, DGAT-I (diacyglycerol acyltransferase-1) and GPAT (glycerol-phosphate acyltransferase), and it is also possible to reduce the intracellular content of neutral lipids, the major targets for curing obesity, by 70%. Therefore, the inventive method may be beneficially used for preventing or treating lipid metabolic diseases including fatty liver, obesity, arteriosclerosis and diabetes.
  • SCDl stearyl CoA desaturase-1
  • DGAT-I diacyglycerol acyltransferase-1
  • GPAT glycerol-phosphate acyltransferase
  • the present invention encompasses, within its scope, a method for screening for a viable lipogenesis inhibitor by treating a subject with candidate inhibitors and analyzing PRP19 gene or its protein expression.
  • the inventive method may comprise the steps of treating cell lines (e.g., differentiated 3T3-L1), tissues, or test animals which express PRP19 protein with candidate inhibitors, and analyzing the changes in PRP19 gene or its protein expression levels by using PRP19 gene or a fragment thereof, or an antibody specific for PRP 19 protein.
  • the expression level of PRP '19 gene or PRP 19 protein may be analyzed using one of the known methods used for detecting gene or protein expression level.
  • PRP19 gene expression may be analyzed by RT-PCR, or blot analysis such as northern blot using PRP19 gene or a fragment thereof as a probe, and PRP 19 protein expression, by way of conducting enzyme-linked immunosorbent assay (ELISA), radioimmunoassay
  • RIA sandwich assay
  • western blot Western blot
  • immunoblot immunohistochemical staining
  • Example 1 The expression level of PRP19 protein by the differentiation of adipocyte
  • Step 1) Cell culture and induction of adipogenic differentiation
  • 3T3-L1 (ATCC No. CL- 173) were maintained in Dulbecco's modified Eagle medium (DMEM, Gibco CA. 1210-0038) supplemented with 10% goat serum under the condition of 37°C and 10% CO 2 until 70% confluency.
  • DMEM Dulbecco's modified Eagle medium
  • 3T3-L1 cells were cultured successively in: DMEM supplemented with 10% FBS, 0.5 mM 3-isobutyl-l-methylxanthine (Sigma), 1 ⁇ M dexamethasone (Sigma) and 167 nM insuline (Novo-Nordisk) for 48 hours; DMEM supplemented with 10% FBS and 167 nM insuline for 48 hours; and DMEM supplemented with 10% FBS for 48 hours, to obtain differetiated adipocytes.
  • 3T3-L1 cells were undergoing adipogenic differentiation for 8 days as described in Step 1), a part of the cells were harvested at intervals of 2 days. Each harvested cell sample was treated with 1 ml of RIPA solution (IxPBS, 1% Nonidet P-40, 0.5% sodium deoxylate and 0.1% SDS), incubated on ice for 30 min, and centrifuged at 15,000xg, 4°C for 10 min to obtain a supernatant. After determining the protein content of the supernatant, 40 ⁇ g of the protein from the supernatant was loaded on 8% SDS-PAGE gel, and transferred to PDF membrane (BioRad) at 50 V for 12 hours.
  • RIPA solution IxPBS, 1% Nonidet P-40, 0.5% sodium deoxylate and 0.1% SDS
  • the transferred membrane was blocked with 5% skim milk solution for 1 hour, and incubated for 1 hour with anti-PRP19 polyclonal antibody (Lab Frontier), anti-perilipin monoclonal antibody (Research Diagnostics), or anti- ⁇ -actin monoclonal antibody (Research Diagnostics) as a primary antibody, and with HRP (horse radish peroxidase)-conjugated anti-rabbit IgG (Amersham) as a secondary antibody.
  • the bound antibody was visualized by the chemiluminescent method using ELC kit (enhanced chemiluminescence kit, Amersham), and the result is shown in FIG. 1.
  • ELC kit enhanced chemiluminescence kit, Amersham
  • the differentiated adipocytes obtained in Step 1) of Example 1 were fixed with 3.7% formaldehyde and washed with PBS 3 times.
  • the fixed cells were blocked with PBS containing 0.1% triton X-100 and 10% FBS for 20 min, and incubated with anti-PRP19 primary antibody and FITC conjugated anti-rabbit IgG secondary antibody (Amersham), followed by adding 0.2% Sudan III to stain neutral lipids.
  • the stained cells were mounted with an anti-fade solution
  • mouse RPRl 9 protein was heavily localized on the surface of lipid droplets surrounding neutral lipids, similarly to most lipid droplet associated proteins.
  • Example 3 Establishment of cell lines expressing PRP 19 siRNA
  • the sequence of PRP 19 siRNA was designed based on PRP19 mRNA sequence using an siRNA design program (http://www.ambion.com/techlib/misc/siRNA_finder.html) provided on the internet by Ambion company, to obtain the nucleotide sequence of SEQ ID NO: 1.
  • the pair of complementary oligonucleotides having SEQ ID NOs: 2 and 3 were designed as a template pair for the above designed siRNA in the custom synthesis conducted by Invitrogen company.
  • the sense and antisense oligonucleotide sequences of the template were designed to comprise: 1) GATC and AGCT sequences on their 5'-ends, respectively, in order to insert the template between the BamHl and Hindlll restriction sites of the commercially available siRNA expression vector, pSilencer 2.1-U6 puro vector (Ambion); and 2) a sequence containing not only the sense sequence for the designed siRNA, but also loop sequence and the antisense sequence for the designed siRNA, so as to express a double stranded siRNA having a hair-pin structure.
  • the complementary oligonucleotides thus synthesized were annealed with each other, and inserted in the ligation-ready pSilencer 2.1-U6 puro (Ambion) using T4 ligase, to obtain a PRP 19 siRNA expression vector named pSi-PRP19.
  • the cleavage map of vector pSi-PRP19 is shown in FIG. 3.
  • the obtained vector was sequenced by the conventional DNA sequencing method to confirm that the construction of the desired vector was indeed achieved, which was transformed into E.coli to be cloned.
  • Step 2) Establishment of a cell line expressing PRP 19 siRNA
  • Some of the differentiated adipocytes obtained in Step 1) of Example 1 were transfected with pSi-PRP19 obtained in Step 1) using liposome (Lipofectamine, Invitrogen), and other cells were transfected with only pSilencer 2.1-U6 puro vector as a control.
  • the transfected cells were cultured in DMEM supplemented with 10% goat serum for 2 days, and then cultured in DMEM containing 3 ⁇ g/ml of puromycin for 10 days to select the transfected cell colonies.
  • the selected colonies were subjected to a western blot analysis as descried in Step 2) of Example 1 to detect PRP 19 protein expression.
  • FIG. 4 As shown in FIG. 4, PRP 19 protein expression was downregulated in the cell line transfected with pSi-PRP19 as compared with the control cell line.
  • Example 4 The effect of downregulation of PRP19 protein on lipid droplet biogenesis
  • the cell line expressing PRP 19 siRNA and the control cell line obtained in Example 3 were fixed with 3.7% formaldehyde and washed 3 times with PBS.
  • FIGs. 5A and 5B are identical to FIGs. 5A and 5B.
  • Example 5 The effect of downregulation of PRP19 protein on the neutral lipid content
  • the cell line expressing PRPl 9 siRNA and the control cell line obtained in Example 3 were each cultured in 100 mm plates and harvested. Each of the harvested cell lines was mixed with 1 ml of a mixture of chloroform and methanol
  • the homogenized cell mixture was centrifiiged at 1,000 rpm for 5 min to take a supernatant, and the supernatant was mixed with 0.2 volume of distilled water and centrifuged at 2,000 rpm for 5 min.
  • the separated lower layer was sampled using a syringe, and the sample was diluted 10 folds with a mixture of chloroform and methanol (2:1, v/v) to measure the intracellular content of neutral lipids.
  • the measurement was performed by applying each diluted sample on a HPTLC (high performance thin layer chromatography) plate using an automated sample applicator (LinomatIV, Camag), and developing the applied sample with automated multiple development chamber (AMD 2, Camag), according to the conventional method (L. Sek et al., J. Pharm. Biomed. Anal. (2001), 25, 651-661).
  • the neutral lipid content of the cell line expressing PRP 19 siRNA was reduced by over 70% in comparison with that of the control cell line.
  • Example 6 The effect of downregulation of PRP19 protein on the expression of lipogenic proteins and genes
  • the cell line expressing PRP 19 siRNA and the control cell line obtained in Example 3 were each subjected to the western blot analysis as in Step 2) of Example 1, except for using anti-perilipin (a known lipid droplet-associated protein, Research Dioagnostics), FAS (fatty acid synthase, BD Biosciences), SCD-I (a key rate-limiting enzyme in the synthesis of unsaturated fatty acids, Alpha Diagnostic International), PPAR- ⁇ (an adipogenic transcription factor, Santa Cruz Biotechnology) or C/EBP- ⁇ (an adiopogenic transcription factor, Santa Cruz Biotechnology) monoclonal antibody as a primary antibody.
  • anti-perilipin a known lipid droplet-associated protein, Research Dioagnostics
  • FAS fatty acid synthase
  • SCD-I a key rate-limiting enzyme in the synthesis of unsaturated fatty acids, Alpha Diagnostic International
  • PPAR- ⁇ an adipogenic transcription factor, Santa Cruz Biotechnology
  • C/EBP- ⁇ an
  • the SCD-I protein expression was much more suppressed in the cell line expressing PRP 19 siRNA as compared to the control cell line, while no significant difference was found in the expressions of FAS, perilipin, PPAR- ⁇ and C/EBP- ⁇ .
  • the cell line expressing PRP19 siRNA and the control cell line obtained in Example 3 were each subjected to RT-PCR (5O 0 C, 2 min; 95 0 C 5 10 min; ⁇ 95°C, 15 sec, 6O 0 C, lmin ⁇ 50 cycles) using commercially available primers (Applied Biosystems) designed to specifically amplify the genes of aP2 and SREBP-Ic known as adipogenic transcription factors, and the genes of DGAT-I and GPAT known as SCD-I down-stream triacylglycerol synthesis enzymes, respectively.
  • RT-PCR 5O 0 C, 2 min; 95 0 C 5 10 min; ⁇ 95°C, 15 sec, 6O 0 C, lmin ⁇ 50 cycles
  • Applied Biosystems designed to specifically amplify the genes of aP2 and SREBP-Ic known as adipogenic transcription factors
  • the genes of DGAT-I and GPAT known as SCD-I down-stream triacylgly
  • the DGAT-I and GPAT mRNA expressions were much more suppressed in the cell line expressing PRPl 9 siRNA as compared to the control cell line, while no significant difference was found in the mRNA expressions of aP2 and SREBP- 1 c.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP06747421A 2005-05-10 2006-05-02 Pharmazeutische zusammensetzung zur hemmung der lipogenese mit einem regulator der prp19-expression Withdrawn EP1888084A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20050038693 2005-05-10
PCT/KR2006/001645 WO2006121250A1 (en) 2005-05-10 2006-05-02 Pharmaceutical composition for the inhibition of lipogenesis comprising a regulator of prp19 expression

Publications (1)

Publication Number Publication Date
EP1888084A1 true EP1888084A1 (de) 2008-02-20

Family

ID=37396727

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06747421A Withdrawn EP1888084A1 (de) 2005-05-10 2006-05-02 Pharmazeutische zusammensetzung zur hemmung der lipogenese mit einem regulator der prp19-expression

Country Status (3)

Country Link
EP (1) EP1888084A1 (de)
CA (1) CA2608120A1 (de)
WO (1) WO2006121250A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9233102B2 (en) 2012-03-07 2016-01-12 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
WO2016022955A1 (en) 2014-08-07 2016-02-11 Mayo Foundation For Medical Education And Research Compounds and methods for treating cancer
CN109425603A (zh) * 2017-08-23 2019-03-05 迪亚莱博（张家港）生物科技有限公司 一种化学发光法快速检测围脂滴蛋白2的试剂盒

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006121250A1 *

Also Published As

Publication number Publication date
WO2006121250A1 (en) 2006-11-16
CA2608120A1 (en) 2006-11-16

Similar Documents

Publication Publication Date Title
Rydén et al. Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis
Lasar et al. Peroxisome proliferator activated receptor gamma controls mature brown adipocyte inducibility through glycerol kinase
Yang et al. Relative contribution of adipose triglyceride lipase and hormone-sensitive lipase to tumor necrosis factor-α (TNF-α)-induced lipolysis in adipocytes
Koh et al. Lipin1 is a key factor for the maturation and maintenance of adipocytes in the regulatory network with CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ2
He et al. MicroRNA-590 attenuates lipid accumulation and pro-inflammatory cytokine secretion by targeting lipoprotein lipase gene in human THP-1 macrophages
Luo et al. MicroRNA-139-5p upregulation is associated with diabetic endothelial cell dysfunction by targeting c-jun
WO2007100789A2 (en) Gpat3 encodes a mammalian, microsomal acyl-coa:glycerol 3-phosphate acyltransferase
Yin et al. FNIP1 regulates adipocyte browning and systemic glucose homeostasis in mice by shaping intracellular calcium dynamics
Liu et al. Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages
Lu et al. QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity
Fu et al. PGC-1α regulates the cell cycle through ATP and ROS in CH1 cells
Wang et al. Triptolide enhances lipolysis of adipocytes by enhancing ATGL transcription via upregulation of p53
Liu et al. Regulation of adipose triglyceride lipase by rosiglitazone
Wang et al. LncRNA TUG1 exacerbates myocardial fibrosis in diabetic cardiomyopathy by modulating the microRNA-145a-5p/Cfl2 axis
Li et al. SEIPIN overexpression in the liver may alleviate hepatic steatosis by influencing the intracellular calcium level
Tsao et al. The critical role of galectin-12 in modulating lipid metabolism in sebaceous glands
Wang et al. Exosomal miR-1246 of adipose stem cells attenuates obesity by polarizing M2 macrophages, reducing fat mass, and Beiging of white adipose tissue
Kurumiya et al. Eliglustat exerts anti-fibrotic effects by activating SREBP2 in TGF-β1-treated myofibroblasts derived from patients with idiopathic pulmonary fibrosis
Shi et al. Adipocyte fatty acid-binding protein: an important gene related to lipid metabolism in chicken adipocytes
WO2006121250A1 (en) Pharmaceutical composition for the inhibition of lipogenesis comprising a regulator of prp19 expression
US20060258609A1 (en) Method for inhibition of lipogenesis by regulating PRP19 expression
EP3220901B1 (de) Mittel und verfahren zur behandlung von frühzeitigem morbus parkinson
JP2011525110A (ja) 心臓病を抑制、遅延、および／または予防するための手段および方法
Harada et al. Readthrough of ACTN3 577X nonsense mutation produces full-length α-actinin-3 protein
Botma et al. Sterol-regulatory-element binding protein inhibits upstream stimulatory factor-stimulated hepatic lipase gene expression

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20071206

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: CHANG, HUI-KYOUNGGEUMHWAMAEUL JUGONG APT.

Inventor name: LEE, HYOUNG-HO

Inventor name: CHO, SI-YOUNG

Inventor name: LEE, TAE-RYONGDONGBO NOBILITY APT. 1201-1602

Inventor name: LEE, JEONG-HOGEUMHWAMAEUL JUGONG APT. 401-405,

Inventor name: SHIN, EUI-SEOKHAMABIMAEUL DONGBU CENTREVILLE APT.

Inventor name: PARK, PIL-JOON

Inventor name: KIM, DAE-GUNDAEWOO HYUNDAI APT. 104-1404

Inventor name: SHIN, DONG-WOOK

Inventor name: CHANG, IH-SEOP

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20090525