PMID- 29162604
OWN - NLM
STAT- MEDLINE
DCOM- 20190129
LR  - 20190129
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 38
IP  - 1
DP  - 2018 Jan
TI  - Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs 
      the Disposal of Remnant Lipoproteins via Syndecan-1.
PG  - 102-113
LID - 10.1161/ATVBAHA.117.310358 [doi]
AB  - OBJECTIVE: Type 2 diabetes mellitus (T2DM) and the atherometabolic syndrome 
      exhibit a deadly dyslipoproteinemia that arises in part from impaired hepatic 
      disposal of C-TRLs (cholesterol- and triglyceride-rich remnant apoB 
      [apolipoprotein B] lipoproteins). We previously identified syndecan-1 as a 
      receptor for C-TRLs that directly mediates endocytosis via rafts, independent 
      from coated pits. Caveolins and flotillins form rafts but facilitate distinct 
      endocytotic pathways. We now investigated their participation in 
      syndecan-1-mediated disposal of C-TRLs and their expression in T2DM liver. 
      APPROACH AND RESULTS: In cultured liver cells and nondiabetic murine livers, we 
      found that syndecan-1 coimmunoprecipitates with FLOT1 (flotillin-1) but not with 
      CAV1 (caveolin-1). Binding of C-TRLs to syndecan-1 on the surface of liver cells 
      enhanced syndecan-1/FLOT1 association. The 2 molecules then trafficked together 
      into the lysosomes, implying limited if any recycling back to the cell surface. 
      The interaction requires the transmembrane/cytoplasmic region of syndecan-1 and 
      the N-terminal hydrophobic domain of FLOT1. Knockdown of FLOT1 in cultured liver 
      cells substantially inhibited syndecan-1 endocytosis. Livers from obese, T2DM 
      KKA(y) mice exhibited 60% to 70% less FLOT1 protein and mRNA than in nondiabetic 
      KK livers. An adenoviral construct to enhance hepatic expression of wild-type 
      FLOT1 in T2DM mice normalized plasma triglycerides, whereas a mutant FLOT1 
      missing its N-terminal hydrophobic domain had no effect. Moreover, the adenoviral 
      vector for wild-type FLOT1 lowered plasma triglyceride excursions and normalized 
      retinyl excursions in T2DM KKA(y) mice after a corn oil gavage, without affecting 
      postprandial production of C-TRLs. CONCLUSIONS: FLOT1 is a novel participant in 
      the disposal of harmful C-TRLs via syndecan-1. Low expression of FLOT1 in T2DM 
      liver may contribute to metabolic dyslipoproteinemia.
CI  - (c) 2017 American Heart Association, Inc.
FAU - Chen, Keyang
AU  - Chen K
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.). chenkeyang@ahmu.edu.cn 
      kjwilliams@temple.edu kevin.jon.williams@gu.se.
FAU - Wu, Qingsi
AU  - Wu Q
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.).
FAU - Hu, Kongwang
AU  - Hu K
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.).
FAU - Yang, Chengwei
AU  - Yang C
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.).
FAU - Wu, Xiangdong
AU  - Wu X
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.).
FAU - Cheung, Peter
AU  - Cheung P
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.).
FAU - Williams, Kevin Jon
AU  - Williams KJ
AD  - From the School of Public Health (K.C., Q.W., C.Y.) and Department of Surgery, 
      The First Affiliated Hospital (K.H.), Anhui Medical University, Hefei, China; 
      Section of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis 
      Katz School of Medicine at Temple University, Philadelphia, PA (K.C., X.W., P.C., 
      K.J.W.); and Department of Molecular and Clinical Medicine, Sahlgrenska Academy 
      of the University of Gothenburg, Sweden (K.J.W.). chenkeyang@ahmu.edu.cn 
      kjwilliams@temple.edu kevin.jon.williams@gu.se.
LA  - eng
GR  - R01 DK100851/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171121
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Chylomicron Remnants)
RN  - 0 (Membrane Proteins)
RN  - 0 (Sdc1 protein, mouse)
RN  - 0 (Syndecan-1)
RN  - 0 (flotillins)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Chylomicron Remnants/*metabolism
MH  - Diabetes Mellitus, Type 2/genetics/*metabolism/therapy
MH  - Disease Models, Animal
MH  - Dyslipidemias/genetics/*metabolism/therapy
MH  - Endocytosis
MH  - Gene Expression Regulation
MH  - Genetic Therapy
MH  - Hepatocytes/*metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - Membrane Proteins/genetics/*metabolism
MH  - Protein Binding
MH  - Protein Interaction Domains and Motifs
MH  - Protein Transport
MH  - Rats
MH  - Signal Transduction
MH  - Syndecan-1/genetics/*metabolism
PMC - PMC5982506
MID - NIHMS920175
OTO - NOTNLM
OT  - cholesterol
OT  - dyslipidemias
OT  - endocytosis
OT  - flotillins
OT  - hypertriglyceridemia
OT  - syndecan-1
OT  - type 2 diabetes mellitus
EDAT- 2017/11/23 06:00
MHDA- 2019/01/30 06:00
PMCR- 2019/01/01
CRDT- 2017/11/23 06:00
PHST- 2017/10/21 00:00 [received]
PHST- 2017/11/07 00:00 [accepted]
PHST- 2017/11/23 06:00 [pubmed]
PHST- 2019/01/30 06:00 [medline]
PHST- 2017/11/23 06:00 [entrez]
PHST- 2019/01/01 00:00 [pmc-release]
AID - ATVBAHA.117.310358 [pii]
AID - 10.1161/ATVBAHA.117.310358 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):102-113. doi: 
      10.1161/ATVBAHA.117.310358. Epub 2017 Nov 21.