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.
复制标题
2 型糖尿病对肝脏 FLOT1 (Flotillin-1) 的抑制会损害 Syndecan-1 对残余脂蛋白的处理
DOI：
10.1161/atvbaha.117.310358
复制
发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Williams KJ
中科院分区：
文献类型：
--
作者：
Chen K;Wu Q;Hu K;Yang C;Wu X;Cheung P;Williams KJ
Type 2 diabetes mellitus (T2DM) and the atherometabolic syndrome exhibit a deadly dyslipoproteinemia that arises in part from impaired hepatic disposal of cholesterol- and triglyceride-rich remnant apoB-lipoproteins (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 T2DM liver. In cultured liver cells and non-diabetic murine livers, we found that syndecan-1 robustly co-immunoprecipitates with flotillin-1 but not with caveolin-1. Binding of C-TRLs to syndecan-1 on liver cells enhanced syndecan-1/flotillin-1 association, and the two 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 flotillin-1. Knock-down of flotillin-1 in cultured liver cells substantially inhibited syndecan-1 endocytosis. Livers from obese, T2DM KKAy mice exhibited 60-70% less flotillin-1 mRNA and protein than in non-diabetic KK livers. An adenoviral construct to enhance hepatic expression of wild-type flotillin-1 in T2DM mice normalized plasma triglycerides, whereas a mutant flotillin-1 missing its N-terminal hydrophobic domain had no effect. Moreover, the adenoviral vector for wild-type flotillin-1 lowered plasma TG excursions and normalized retinyl excursions in T2DM KKAy mice after corn-oil gavage, without affecting postprandial production of C-TRLs. Flotillin-1 is a novel participant in the disposal of harmful C-TRLs via syndecan-1. Low expression of flotillin-1 in T2DM liver may contribute to metabolic dyslipoproteinemia.
