Suppression Of Hepatic FLOT1(Flotillin-1) By Type 2 Diabetes Mellitus Impairs The Disposal Of Remnant Lipoproteins Via Syndecan-1

Objective T2 DM and the atherometabolic syndrome exhibit a deadly dyslipoproteinemia that arises in part from impaired hepatic disposal of C-TRLs.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 T2 DM liver.Approach and Results In cultured liver cells and nondiabetic murine livers,we found that Syndecan-1 coimmunoprecipitates with FLOT1 but not with CAV1.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 N-terminal hydrophobic domain of FLOT1.Knockdown of FLOT1 in cultured liver cells substantially inhibited Syndecan-1 endocytosis.Livers from obese,T2 DM KKAy mice exhibited 60% to 70% less FLOT1 protein and m RNA than in nondiabetic KK livers.An adenoviral construct to enhance hepatic expression of wild-type FLOT1 in T2 DM mice normalized plasma triglycerides,whereas a mutant FLO T1 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 T2 DM KKAy mice after a corn oil gavage.Conclusions FLOT1 is a novel participant in the disposal of harmful C-TRLs via Syndecan-1.Low expression of FLO T1 in T2 DM liver may contribute to metabolic dyslipoproteinemia.