PMID- 26495026
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151023
LR  - 20210216
IS  - 1743-7075 (Print)
IS  - 1743-7075 (Electronic)
IS  - 1743-7075 (Linking)
VI  - 12
DP  - 2015
TI  - Hepatic S1P deficiency lowers plasma cholesterol levels in apoB-containing 
      lipoproteins when LDLR function is compromised.
PG  - 35
LID - 10.1186/s12986-015-0031-4 [doi]
LID - 35
AB  - BACKGROUND: Site-1 protease (S1P) is the key enzyme required for activation of 
      the sterol regulatory element binding proteins (SREBPs) that govern lipid 
      synthesis. While S1P has been speculated to influence plasma apoB-containing 
      lipoprotein (Blp) metabolism, there has been little investigative work. LDL 
      receptor (LDLR) is the major receptor for clearing plasma LDL cholesterol 
      (LDL-c). Proprotein convertase subtilisin kexin type 9 (PCSK9) modulates LDL-c 
      through post-translational degradation of the LDLR. METHODS: A hepatic-specific 
      knockdown (KD) of S1P was achieved using floxed S1P mouse models (S1P(f/f) and 
      LDLR(-/-)S1P(f/f)) and hepatic expression of Cre recombinase. Lipids were 
      measured in total plasma and size fractionated plasma using colorimetric assays. 
      Realtime polymerase chain reaction, western blotting and ELISA were used to 
      determine hepatic expression of key genes/protein. Plasmid mediated 
      overexpression and siRNA mediated knockdown of genes were performed in mouse 
      primary hepatocytes to determine the mechanistic basis of PCSK9 gene regulation. 
      RESULTS: A hepatic-specific KD of S1P resulted in a 45 % and 38 % reduction in 
      plasma total cholesterol and triglyceride levels, respectively. Hepatic S1P KD 
      had a minimal effect on plasma Blp cholesterol (Blp-c) in S1P(f/f) mice, despite 
      significantly reducing VLDL secretion. Notably, hepatic S1P KD decreased the LDL 
      receptor (LDLR) mRNA expression by 50 %. However, the reduction in LDLR protein 
      levels was less than that of mRNA expression, especially under fed conditions. 
      Further assessment of hepatic S1P deficiency revealed that it increased LDLR 
      protein stability in vivo. Mechanistically, hepatic S1P KD was shown to decrease 
      the liver and plasma levels of the protein proprotein convertase subtilisin/kexin 
      type 9 (PCSK9), which degrades LDLR protein. This effect was more prominent in 
      the fed condition and sufficient to account for the discordance in LDLR mRNA and 
      protein levels. Furthermore, hepatic S1P was shown to regulate PCSK9 expression 
      through activation of the SREBPs. In the LDLR(-/-) background, hepatic S1P KD 
      significantly reduced Blp-c levels. CONCLUSION: Hepatic S1P is a physiological 
      modulator of plasma Blp metabolism through its regulation of LDLR and PCSK9. 
      Hepatic S1P is a valid target for lowering plasma Blp-c levels in the situation 
      where LDLR function is compromised.
FAU - Basu, Debapriya
AU  - Basu D
AD  - Department of Cell Biology, State University of New York, Downstate Medical 
      Center, Brooklyn, NY 11203 USA.
FAU - Huq, Afroza
AU  - Huq A
AD  - Department of Cell Biology, State University of New York, Downstate Medical 
      Center, Brooklyn, NY 11203 USA.
FAU - Iqbal, Jahangir
AU  - Iqbal J
AD  - Department of Cell Biology, State University of New York, Downstate Medical 
      Center, Brooklyn, NY 11203 USA ; Department of Pediatrics, State University of 
      New York, Downstate Medical Center, Brooklyn, NY 11203 USA.
FAU - Hussain, M Mahmood
AU  - Hussain MM
AD  - Department of Cell Biology, State University of New York, Downstate Medical 
      Center, Brooklyn, NY 11203 USA ; Department of Pediatrics, State University of 
      New York, Downstate Medical Center, Brooklyn, NY 11203 USA.
FAU - Jiang, Xian-Cheng
AU  - Jiang XC
AD  - Department of Cell Biology, State University of New York, Downstate Medical 
      Center, Brooklyn, NY 11203 USA.
FAU - Jin, Weijun
AU  - Jin W
AD  - Department of Cell Biology, State University of New York, Downstate Medical 
      Center, Brooklyn, NY 11203 USA.
LA  - eng
GR  - I01 BX000900/BX/BLRD VA/United States
GR  - R01 HL081861/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20151020
PL  - England
TA  - Nutr Metab (Lond)
JT  - Nutrition & metabolism
JID - 101231644
PMC - PMC4613744
OTO - NOTNLM
OT  - Ad libitum
OT  - Blp-c
OT  - Hepatocytes
OT  - Knockdown
OT  - LDLR
OT  - PCSK9
OT  - S1P
OT  - SREBP
OT  - cre
EDAT- 2015/10/27 06:00
MHDA- 2015/10/27 06:01
PMCR- 2015/10/20
CRDT- 2015/10/24 06:00
PHST- 2015/04/22 00:00 [received]
PHST- 2015/09/28 00:00 [accepted]
PHST- 2015/10/24 06:00 [entrez]
PHST- 2015/10/27 06:00 [pubmed]
PHST- 2015/10/27 06:01 [medline]
PHST- 2015/10/20 00:00 [pmc-release]
AID - 31 [pii]
AID - 10.1186/s12986-015-0031-4 [doi]
PST - epublish
SO  - Nutr Metab (Lond). 2015 Oct 20;12:35. doi: 10.1186/s12986-015-0031-4. eCollection 
      2015.