The overwhelming majority of patients with type 2 diabetes mellitus (T2DM) and related syndromes die from accelerated atherosclerosis. These patients exhibit a striking persistence of postprandial TG-rich lipoproteins, called 'remnants,'in their plasma after each meal. Importantly, remnants have been linked to human cardiovascular events. Because the basis for delayed remnant clearance in T2DM patients has been poorly understood, no therapeutic strategies are available to target these harmful particles. Our laboratory has made a series of fundamental advances in this area. First, we identified the syndecan-1 heparan sulfate proteoglycan (HSPG) as a remnant receptor. Second, using an array, we found dysregulation of exactly one gene that would impair syndecan-1 function in remnant clearance - namely, sulfatase-2 (Sulf2), which is 10-fold overexpressed in T2DM liver. SULF2 impedes syndecan-1-mediated catabolism of remnants by liver cells. Third, we just published that inhibition of hepatic Sulf2 in vivo flattens plasma TG excursions after corn-oil gavage in T2DM mice. Fourth, we discovered that insulin suppresses SULF2 protein posttranscriptionally, and that this effect becomes insulin-resistant in T2DM liver owing to a defect in NOX4 function that impairs AKT activation. By focusing on SULF2, we will improve our under- standing of postprandial dyslipidemia and facilitate the translation of our work into clinicl utility.
Aim 1 : Role of sulfatase-2 in atherosclerosis: lipoprotein and non-lipoprotein effects. Hypothesis 1: Inhibition of SULF2 will slow atherosclerosis through two effects: in the liver by improving the plasma lipoprotein profile and in the arterial wall by impeding local pro-atherogenic signaling pathways, particularly Wnt. We will examine atherosclerotic lesion development in SULF2-deficient mice, bred into major atherosclerosis models. Beneficial effects of SULF2 deficiency will further bolster our therapeutic focus.
Aim 2 : Molecular mechanisms for overexpression of sulfatase-2 in T2DM liver. Hypothesis 2: Hepatic SULF2 overexpression in T2DM occurs through key nodes that are potential therapeutic targets. We will define the crucial signaling intermediates downstream of the insulin receptor that normally suppress SULF2, as well as novel molecular mediators that affect SULF2 protein synthesis and degradation.
Aim 3 : Novel strategies to correct hepatic SULF2 overexpression in T2DM liver, and hence attenuate postprandial dyslipoproteinemia. Hypothesis 3: Inhibition of SULF2 is a viable therapeutic strategy, and we will take this concept beyond our previous ASO method.
In Aim 3 a, we will correct hepatic insulin signaling defects in T2DM liver in vivo, focusing on chaperones of NOX4 that are dysregulated in T2DM.
Aim 3 b will manipulate in vivo the novel participants in SULF2 regulation that we identify in Aim 2. Overall, these proposed Aims will substantially advance our molecular understanding and our abilities to correct the devastating burden of accelerated atherosclerosis in T2DM.
The overwhelming majority of patients with type 2 diabetes mellitus (T2DM) and related syndromes die from accelerated atherosclerosis that arises, in part, from the striking persistence of harmful intestinally derived lipoproteins, called 'remnants,'in their plasma after each meal. In two major advances, we discovered that syndecan-1 mediates the healthy, rapid disposal of remnants by the liver, but T2DM livers overexpress sulfatase-2, a novel inhibitor of syndecan-1. Building on these discoveries, the research in this proposal will substantially advance our molecular understanding and our abilities to correct the devastating burden of accelerated atherosclerosis in T2DM.
|Chen, Keyang; Wu, Qingsi; Hu, Kongwang et al. (2018) Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1. Arterioscler Thromb Vasc Biol 38:102-113|
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|Li, Mingzhen; Li, Chunjun; Liu, Yu et al. (2015) Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposure. Nutr Metab (Lond) 12:15|
|Hassing, H Carlijne; Surendran, R Preethi; Derudas, Bruno et al. (2014) SULF2 strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus. Obesity (Silver Spring) 22:1309-16|