PMID- 10600799
OWN - NLM
STAT- MEDLINE
DCOM- 20000120
LR  - 20181130
IS  - 0002-9513 (Print)
IS  - 0002-9513 (Linking)
VI  - 277
IP  - 6
DP  - 1999 Dec
TI  - Cyclosporin-induced dyslipoproteinemia is associated with selective activation of
      SREBP-2.
PG  - E1087-94
LID - 10.1152/ajpendo.1999.277.6.E1087 [doi]
AB  - The use of cyclosporin A has contributed greatly to the success of organ
      transplantation. However, cyclosporin-associated side effects of hypertension,
      nephrotoxicity, and dyslipoproteinemia have tempered these benefits.
      Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the
      accelerated atherosclerosis observed posttransplantation. Using a mouse model, we
      treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of
      cyclosporin and observed significant elevations of plasma cholesterol,
      triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone
      treated control animals. Measurement of the rate of secretion of very low-density
      lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to 
      a significant increase in the rate of hepatic VLDL triglyceride secretion. Total 
      apoB secretion was unaffected. Northern analysis showed that cyclosporin A
      treatment increased the abundance of hepatic mRNA levels for a number of key
      genes involved in cholesterol biosynthesis relative to vehicle-alone treated
      animals. Two key transcriptional factors, sterol regulatory element-binding
      protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2
      expression was increased at the mRNA level, and there was an increase in the
      active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were
      reduced. These results show that the molecular mechanisms by which cyclosporin
      causes dyslipoproteinemia may, in part, be mediated by selective activation of
      SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic
      secretion of VLDL triglyceride.
FAU - Wu, J
AU  - Wu J
AD  - Division of Endocrinology, Diabetes, and Medical Genetics, Medical University of 
      South Carolina, Charleston, South Carolina 29425-2222, USA.
FAU - Zhu, Y H
AU  - Zhu YH
FAU - Patel, S B
AU  - Patel SB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Physiol
JT  - The American journal of physiology
JID - 0370511
RN  - 0 (Apolipoprotein B-100)
RN  - 0 (Apolipoprotein B-48)
RN  - 0 (Apolipoproteins B)
RN  - 0 (Cholesterol, VLDL)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fatty Acids)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, LDL)
RN  - 0 (Srebf2 protein, mouse)
RN  - 0 (Sterol Regulatory Element Binding Protein 2)
RN  - 0 (Sterols)
RN  - 0 (Transcription Factors)
RN  - 0 (Triglycerides)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.13.- (oxysterol 7-alpha-hydroxylase)
RN  - EC 1.14.19.1 (Stearoyl-CoA Desaturase)
RN  - EC 2.3.1.85 (Fatty Acid Synthases)
RN  - EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase)
RN  - EC 3.1.1.3 (Lipase)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
SB  - IM
MH  - Acetyl-CoA Carboxylase/genetics
MH  - Animals
MH  - Apolipoprotein B-100
MH  - Apolipoprotein B-48
MH  - Apolipoproteins B/metabolism
MH  - Cholesterol, VLDL/metabolism
MH  - Coronary Disease/chemically induced/metabolism
MH  - Cyclosporine/*adverse effects
MH  - *Cytochrome P-450 Enzyme System
MH  - DNA-Binding Proteins/*genetics
MH  - Farnesyl-Diphosphate Farnesyltransferase/genetics
MH  - Fatty Acid Synthases/genetics
MH  - Fatty Acids/biosynthesis/metabolism
MH  - Female
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Hydroxymethylglutaryl CoA Reductases/genetics
MH  - Hyperlipoproteinemias/*chemically induced/*metabolism
MH  - Immunosuppressive Agents/*adverse effects
MH  - Immunotherapy/adverse effects
MH  - Leucine Zippers/genetics
MH  - Lipase/genetics
MH  - Liver/enzymology/metabolism
MH  - Mice
MH  - RNA, Messenger/analysis
MH  - Receptors, LDL/genetics
MH  - Stearoyl-CoA Desaturase/genetics
MH  - Steroid Hydroxylases/genetics
MH  - Sterol Regulatory Element Binding Protein 2
MH  - Sterols/biosynthesis/metabolism
MH  - Transcription Factors/*genetics
MH  - Transcription, Genetic/drug effects
MH  - Triglycerides/metabolism
EDAT- 1999/12/22 00:00
MHDA- 1999/12/22 00:01
CRDT- 1999/12/22 00:00
PHST- 1999/12/22 00:00 [pubmed]
PHST- 1999/12/22 00:01 [medline]
PHST- 1999/12/22 00:00 [entrez]
AID - 10.1152/ajpendo.1999.277.6.E1087 [doi]
PST - ppublish
SO  - Am J Physiol. 1999 Dec;277(6):E1087-94. doi: 10.1152/ajpendo.1999.277.6.E1087.