Abstract
ObjectiveHigh density lipoprotein (HDL) cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein) mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/-) model fed a high fat high sucrose with cholesterol (HFHSC) diet.MethodsStudies in differentiated 3T3-L1 adipocytes tested whether L4F could inhibit palmitate-induced adipocyte inflammation. In vivo studies used male Ldlr-/- mice fed a HFHSC diet for 12 weeks and were injected daily with L4F (100 µg/mouse) subcutaneously during the last 8 weeks. Wild-type and apoA-I overexpressing Ldlr-/- mice were fed HFHSC diet for 16 weeks.ResultsNeither L4F administration nor apoA-I overexpression affected weight gain, total plasma cholesterol or triglycerides in our studies. While pre-treatment of 3T3-L1 adipocytes with either L4F or HDL abolished palmitate-induced cytokine expression in vitro, L4F treatment did not affect circulating or adipose tissue inflammatory markers in vivo. Neither L4F administration nor apoA-I overexpression affected glucose tolerance. ApoA-I overexpression significantly reduced atherosclerotic lesion size, yet L4F treatment did not affect atherosclerosis.ConclusionOur results suggest that neither L4F (100 µg/day/mouse) nor apoA-I overexpression affects adiposity or insulin resistance in this model. We also were unable to confirm a reduction in atherosclerosis with L4F in our particular model. Further studies on the effect of apoA-I mimetics on atherosclerosis and insulin resistance in a variety of dietary contexts are warranted.
Highlights
The strong inverse relationship between high density lipoprotein (HDL) cholesterol levels and coronary heart disease [1] has been known for over three decades
We previously have shown that palmitate induces chemotactic factor expression in 3T3-L1 adipocytes [15] and this can be inhibited by pre-treatment with HDL [6]
Treatment of Ldlr-/- mice with L4F peptide given at 100 mg/day/mouse had no impact on the extent of weight gain, compared with the saline injected animals
Summary
The strong inverse relationship between high density lipoprotein (HDL) cholesterol levels and coronary heart disease [1] has been known for over three decades. Recent research has highlighted other functional properties of HDL, including its anti-inflammatory and anti-oxidant activities, as additional mechanisms to reduce atherosclerosis [3]. Low HDL cholesterol levels are associated with development of type 2 diabetes mellitus (T2DM) [4]. Inflammation has been suggested to be responsible for the reduction in HDL levels seen in the setting of insulin resistance and obesity [5]. Recent data have highlighted antiinflammatory properties of HDL [6], suggesting HDL may improve insulin sensitivity [7]
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