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

Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1.
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Chen K, Wu Q, Hu K, Yang C, Wu X, Cheung P, Williams KJ,


Chen K, Wu Q, Hu K, Yang C, Wu X, Cheung P, Williams KJ, (click to view)

Chen K, Wu Q, Hu K, Yang C, Wu X, Cheung P, Williams KJ,

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Arteriosclerosis, thrombosis, and vascular biology 2017 11 21() pii ATVBAHA.117.310358
Abstract
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 robustly coimmunoprecipitates with FLOT1 (flotillin-1) but not with CAV1 (caveolin-1). Binding of C-TRLs to syndecan-1 on liver cells enhanced syndecan-1/FLOT1 association, and 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 mRNA and protein 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 TG excursions and normalized retinyl excursions in T2DM KKA(y) mice after 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.

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