PMID- 29700117
OWN - NLM
STAT- MEDLINE
DCOM- 20190122
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 24
DP  - 2018 Jun 15
TI  - Sterol carrier protein-2 deficiency attenuates diet-induced dyslipidemia and 
      atherosclerosis in mice.
PG  - 9223-9231
LID - 10.1074/jbc.RA118.002290 [doi]
AB  - Intracellular cholesterol transport proteins move cholesterol to different 
      subcellular compartments and thereby regulate its final metabolic fate. In 
      hepatocytes, for example, delivery of high-density lipoprotein (HDL)-associated 
      cholesterol for bile acid synthesis or secretion into bile facilitates 
      cholesterol elimination from the body (anti-atherogenic effect), whereas delivery 
      for esterification and subsequent incorporation into apolipoprotein B-containing 
      atherogenic lipoproteins (e.g. very-low-density lipoprotein (VLDL)) enhances 
      cholesterol secretion into the systemic circulation (pro-atherogenic effect). 
      Intracellular cholesterol transport proteins such as sterol carrier protein-2 
      (SCP2) should, therefore, play a role in regulating these pro- or 
      anti-atherosclerotic processes. Here, we sought to evaluate the effects of SCP2 
      deficiency on the development of diet-induced atherosclerosis. We generated 
      LDLR(-/-) mice deficient in SCP2/SCPx (LS) and examined the effects of this 
      deficiency on Western diet-induced atherosclerosis. SCP2/SCPx deficiency 
      attenuated atherosclerosis in LS mice by >80% and significantly reduced plasma 
      cholesterol and triglyceride levels. Investigation of the likely underlying 
      mechanisms revealed a significant reduction in intestinal cholesterol absorption 
      (given as an oral gavage) in SCP2/SCPx-deficient mice. Consistently, 
      siRNA-mediated knockdown of SCP2 in intestinal cells significantly reduced 
      cholesterol uptake. Furthermore, hepatic triglyceride/VLDL secretion from the 
      liver or hepatocytes isolated from SCP2/SCPx-deficient mice was significantly 
      reduced. These results indicate an important regulatory role for SCP2 deficiency 
      in attenuating diet-induced atherosclerosis by limiting intestinal cholesterol 
      absorption and decreasing hepatic triglyceride/VLDL secretion. These findings 
      suggest targeted inhibition of SCP2 as a potential therapeutic strategy to reduce 
      Western diet-induced dyslipidemia and atherosclerosis.
FAU - He, Hongliang
AU  - He H
AD  - From the Departments of Internal Medicine and.
FAU - Wang, Jing
AU  - Wang J
AD  - From the Departments of Internal Medicine and.
FAU - Yannie, Paul J
AU  - Yannie PJ
AD  - the Hunter Homes McGuire Veterans Affairs Medical Center, Richmond, Virginia 
      23249.
FAU - Kakiyama, Genta
AU  - Kakiyama G
AD  - the Hunter Homes McGuire Veterans Affairs Medical Center, Richmond, Virginia 
      23249.
FAU - Korzun, William J
AU  - Korzun WJ
AD  - Clinical and Laboratory Sciences, Virginia Commonwealth University (VCU) Medical 
      Center, Richmond, Virginia 23298 and.
FAU - Ghosh, Shobha
AU  - Ghosh S
AD  - From the Departments of Internal Medicine and shobha@vcu.edu.
AD  - the Hunter Homes McGuire Veterans Affairs Medical Center, Richmond, Virginia 
      23249.
LA  - eng
GR  - R01 HL097346/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180426
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (Lipoproteins, VLDL)
RN  - 0 (Triglycerides)
RN  - 0 (sterol carrier proteins)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/blood/*etiology/genetics/*metabolism
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cholesterol/blood/metabolism
MH  - Diet, Western/*adverse effects
MH  - Dyslipidemias/blood/*etiology/genetics/*metabolism
MH  - Female
MH  - Gene Deletion
MH  - Intestinal Absorption
MH  - Lipoproteins, VLDL/metabolism
MH  - Liver/metabolism
MH  - Male
MH  - Mice
MH  - Triglycerides/blood/metabolism
PMC - PMC6005425
OTO - NOTNLM
OT  - anti-atherogenic effect
OT  - atherosclerosis
OT  - cardiovascular disease
OT  - cholesterol metabolism
OT  - cholesterol-binding protein
OT  - diet
OT  - dyslipidemia
OT  - hepatic VLDL secretion
OT  - intracellular cholesterol transport
OT  - sterol carrier protein
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article. The content is solely the responsibility of the authors and does 
      not necessarily represent the official views of the National Institutes of Health
EDAT- 2018/04/28 06:00
MHDA- 2019/01/23 06:00
PMCR- 2018/04/26
CRDT- 2018/04/28 06:00
PHST- 2018/02/05 00:00 [received]
PHST- 2018/04/25 00:00 [revised]
PHST- 2018/04/28 06:00 [pubmed]
PHST- 2019/01/23 06:00 [medline]
PHST- 2018/04/28 06:00 [entrez]
PHST- 2018/04/26 00:00 [pmc-release]
AID - S0021-9258(20)38895-5 [pii]
AID - RA118.002290 [pii]
AID - 10.1074/jbc.RA118.002290 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Jun 15;293(24):9223-9231. doi: 10.1074/jbc.RA118.002290. Epub 
      2018 Apr 26.