PMID- 32819213
OWN - NLM
STAT- MEDLINE
DCOM- 20210524
LR  - 20211010
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 127
IP  - 9
DP  - 2020 Oct 9
TI  - Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles.
PG  - 1198-1210
LID - 10.1161/CIRCRESAHA.120.317178 [doi]
AB  - RATIONALE: HDL (high-density lipoprotein) may be cardioprotective because it 
      accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 
      (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter 
      G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL 
      strongly and negatively associates with cardiovascular disease risk, but how 
      diabetes mellitus impacts that step is unclear. OBJECTIVE: To test the hypothesis 
      that HDL's cholesterol efflux capacity is impaired in subjects with type 2 
      diabetes mellitus. METHODS AND RESULTS: We performed a case-control study with 19 
      subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of 
      HDL particles, small HDL, medium HDL, and large HDL, were isolated by 
      high-resolution size exclusion chromatography from study subjects. Then we 
      assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL 
      accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC-but not ABCG1 
      CEC-of small HDL was lower in the subjects with type 2 diabetes mellitus than the 
      control subjects. Isotope dilution tandem mass spectrometry demonstrated that the 
      concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower 
      in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced 
      ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic alpha-helices 
      clustered in the N-terminal domain of the protein; biochemical analyses 
      demonstrated that SERPINA1 binds phospholipid vesicles. CONCLUSIONS: The ABCA1 
      CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely 
      because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic 
      alpha-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 
      activity. Thus, impaired ABCA1 activity of small HDL particles deficient in 
      SERPINA1 could increase cardiovascular disease risk in subjects with diabetes 
      mellitus.
FAU - He, Yi
AU  - He Y
AD  - Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., 
      V.K., K.E.B., J.W.H.).
FAU - Ronsein, Graziella E
AU  - Ronsein GE
AD  - Department of Biochemistry, University of Sao Paulo, Brazil (G.E.R.).
FAU - Tang, Chongren
AU  - Tang C
AD  - Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., 
      V.K., K.E.B., J.W.H.).
FAU - Jarvik, Gail P
AU  - Jarvik GP
AD  - Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., 
      V.K., K.E.B., J.W.H.).
FAU - Davidson, W Sean
AU  - Davidson WS
AD  - Department of Medicine, University of Cincinnati, OH (W.S.D.).
FAU - Kothari, Vishal
AU  - Kothari V
AD  - Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., 
      V.K., K.E.B., J.W.H.).
FAU - Song, Hyun D
AU  - Song HD
AD  - Department of Medicine, Vanderbilt University, Nashville, TN (H.D.S., J.P.S.).
FAU - Segrest, Jere P
AU  - Segrest JP
AD  - Department of Medicine, Vanderbilt University, Nashville, TN (H.D.S., J.P.S.).
FAU - Bornfeldt, Karin E
AU  - Bornfeldt KE
AD  - Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., 
      V.K., K.E.B., J.W.H.).
FAU - Heinecke, Jay W
AU  - Heinecke JW
AD  - Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., 
      V.K., K.E.B., J.W.H.).
LA  - eng
GR  - P01 HL128203/HL/NHLBI NIH HHS/United States
GR  - T32 HL007828/HL/NHLBI NIH HHS/United States
GR  - R01 HL108897/HL/NHLBI NIH HHS/United States
GR  - P01 HL092969/HL/NHLBI NIH HHS/United States
GR  - P30 DK017047/DK/NIDDK NIH HHS/United States
GR  - R01 HL112625/HL/NHLBI NIH HHS/United States
GR  - R01 HL149685/HL/NHLBI NIH HHS/United States
GR  - DP3 DK108209/DK/NIDDK NIH HHS/United States
GR  - P01 HL076491/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 - 20200821
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (ABCG1 protein, human)
RN  - 0 (ATP Binding Cassette Transporter 1)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1)
RN  - 0 (Apolipoprotein C-II)
RN  - 0 (Apolipoproteins)
RN  - 0 (Lipoproteins, HDL)
RN  - 0 (Phospholipids)
RN  - 0 (SERPINA1 protein, human)
RN  - 0 (Triglycerides)
RN  - 0 (alpha 1-Antitrypsin)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - ATP Binding Cassette Transporter 1/*metabolism
MH  - ATP Binding Cassette Transporter, Subfamily G, Member 1/*metabolism
MH  - Apolipoprotein C-II/analysis
MH  - Apolipoproteins/metabolism
MH  - Cardiovascular Diseases/*etiology
MH  - Case-Control Studies
MH  - Cholesterol/*metabolism
MH  - Diabetes Mellitus, Type 2/blood/*metabolism
MH  - Female
MH  - Humans
MH  - Lipoproteins, HDL/*metabolism
MH  - Macrophages/metabolism
MH  - Male
MH  - Middle Aged
MH  - Phospholipids/metabolism
MH  - Protein Structure, Tertiary
MH  - Risk
MH  - Triglycerides/analysis
MH  - alpha 1-Antitrypsin/chemistry/*metabolism
PMC - PMC7554159
MID - NIHMS1622603
OTO - NOTNLM
OT  - diabetes mellitus
OT  - prevalence
OT  - proteomics
OT  - serpins
OT  - tandem mass spectrometry
EDAT- 2020/08/21 06:00
MHDA- 2021/05/25 06:00
PMCR- 2021/10/09
CRDT- 2020/08/22 06:00
PHST- 2020/08/21 06:00 [pubmed]
PHST- 2021/05/25 06:00 [medline]
PHST- 2020/08/22 06:00 [entrez]
PHST- 2021/10/09 00:00 [pmc-release]
AID - 10.1161/CIRCRESAHA.120.317178 [doi]
PST - ppublish
SO  - Circ Res. 2020 Oct 9;127(9):1198-1210. doi: 10.1161/CIRCRESAHA.120.317178. Epub 
      2020 Aug 21.