Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1

Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):102-113. doi: 10.1161/ATVBAHA.117.310358. Epub 2017 Nov 21.


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 KKAy 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 KKAy 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.

Keywords: cholesterol; dyslipidemias; endocytosis; flotillins; hypertriglyceridemia; syndecan-1; type 2 diabetes mellitus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chylomicron Remnants / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / therapy
  • Disease Models, Animal
  • Dyslipidemias / genetics
  • Dyslipidemias / metabolism*
  • Dyslipidemias / therapy
  • Endocytosis
  • Gene Expression Regulation
  • Genetic Therapy
  • Hepatocytes / metabolism*
  • Liver / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Rats
  • Signal Transduction
  • Syndecan-1 / genetics
  • Syndecan-1 / metabolism*


  • Chylomicron Remnants
  • Membrane Proteins
  • Sdc1 protein, mouse
  • Syndecan-1
  • flotillins