Dietary Sucrose but not Starch Promotes Protein-Induced Differences in Rates of VLDL Secretion and Plasma Lipid Concentrations in Rats

Type 1 diabetes (T1D) increases the risk of adverse coronary events. Among risk factors, dyslipidemia due to altered hepatic lipoprotein metabolism plays a central role in diabetic atherosclerosis. Nevertheless, the likely alterations in plasma lipid/lipoprotein profile remain unclear, especially in the context of spontaneously developed T1D and atherosclerosis. To address this question, we generated Ins2+/Akita:apoE−/− mouse by cross-breeding Ins2+/Akita mouse (which has Ins2 gene mutation, causing pancreatic β-cell apoptosis and insulin deficiency) with apoE−/− mouse. Ins2+/Akita:apoE−/− mice developed T1D spontaneously at 4–5 wk of age. At 25 wk of age and while on a standard chow diet, diabetic Ins2+/Akita:apoE−/− mice exhibited an approximately threefold increase in atherosclerotic plaque in association with an approximatelty twofold increase in plasma non-HDL cholesterol, predominantly in the LDL fraction, compared with nondiabetic controls. To determine factors contributing to the exaggerated hypercholesterolemia, we assessed hepatic VLDL secretion and triglyceride content, expression of hepatic lipoprotein receptors, and plasma apolipoprotein composition. Diabetic Ins2+/Akita:apoE−/− mice exhibited diminished VLDL secretion by ∼50%, which was accompanied by blunted Akt phosphorylation in response to insulin infusion and decreased triglyceride content in the liver. Although the expression of hepatic LDL receptor was not affected, there was a significant reduction in the expression of lipolysis-stimulated lipoprotein receptor (LSR) by ∼28%. Moreover, there was a marked decrease in plasma apoB-100 with a significant increase in apoB-48 and apoC-III levels. In conclusion, exaggerated hypercholesterolemia and atherosclerosis in spontaneously diabetic Ins2+/Akita:apoE−/− mice may be attributable to impaired lipoprotein clearance in the setting of diminished expression of LSR and altered apolipoprotein composition of lipoproteins.

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Abstract 387: Regulation of Apolipoprotein B Secretion by Hepatic Sortilin is Dependent on Secretory Stress

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.387 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Donna Conlon ◽

Amrith Rodrigues ◽

Alanna Strong ◽

Nicholas Hand ◽

Daniel Rader

Keyword(s):

Plasma Lipid ◽

Metabolic Stress ◽

Primary Hepatocytes ◽

Over Expression ◽

Vldl Secretion ◽

Sorting Receptor ◽

Apob Secretion ◽

Artery Disease

Sortilin is a multi-ligand sorting receptor involved in trafficking of proteins from the Golgi apparatus to the lysosome and has been widely shown to be associated with plasma lipid traits and coronary artery disease. While over expression of sortilin in the liver reduces VLDL production, the reported effects of the genetic loss of sortilin on apolipoprotein B100 (apoB) and VLDL secretion have been contradictory and perplexing; loss of sortilin has been shown in different studies to result in both increased and decreased apoB/VLDL secretion. These conflicting studies were carried out in a variety of different models and used different methods of knocking down sortilin expression. To attempt to further clarify the role of sortilin, we explored the role of sortilin deficiency on apoB secretion in the hepatocyte by utilizing 2 in vitro models of sortilin knockdown; primary hepatocytes from Sort1-/- mice and siRNA -treated McA-RH7777 (McA) cells. In both primary hepatocytes and McA cells, loss of sortilin alone was not associated with any change in apoB secretion. The previously reported increases in VLDL secretion occurred on either the background of apoB over expression or in livers of mice on a high fat diet, suggesting the requirement for a metabolic stress. We found that apoB secretion was increased with Sort1 knockdown as compared to control in isolated primary hepatocytes from Apobec1-/-; hAPOB Tg mice and McA cells stably over expressing apoB. We then sought to increase apoB secretion by lipid loading with oleic acid (OA). While OA increased apoB secretion in all cells, there was no effect of Sort1 knockdown in this context. However, when the cells were further treated with either palmitic acid, proteasomal inhibitors, or tunicamycin (an ER stress inducer), there was an observed increase in apoB secretion with Sort1 knockdown, suggesting that sortilin regulates apoB secretion only when both apoB secretion is increased and the cell is stressed. Based on this data, we propose that hepatic sortilin regulates the post-ER fate of apoB for degradation and export and acts to coordinate intracellular apoB metabolism in response to the number and quality of apoB particles that reach the Golgi and the level of post-ER pre-secretory proteolysis activity.

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Abstract 49: Myeloid Cell Specific ABCA1 Deletion Does Not Significantly Accelerate Atherogenesis in LDL Receptor Knockout Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a49 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Xin Bi ◽

Xuewei Zhu ◽

Chuan Gao ◽

Qiang Cao ◽

Mingxia Liu ◽

...

Keyword(s):

Inflammatory Response ◽

Ldl Receptor ◽

Plasma Lipid ◽

Myeloid Cell ◽

Cholesterol Content ◽

Peritoneal Macrophages ◽

Atherogenic Diet ◽

Cellular Cholesterol ◽

Vldl Secretion

ATP binding cassette transporter A1 (ABCA1) functions as a cellular cholesterol exporter. Macrophage ABCA1 expression is important in reducing cellular cholesterol content and inflammatory response. Bone marrow (BM) transplantation studies suggest that leukocyte ABCA1 protects against atherosclerosis development. However, the in vivo effect of macrophage ABCA1 in atherogenesis is not fully understood due to the presence in BM of other leukocyte populations. Myeloid[[Unable to Display Character: ‐]]Specific ABCA1 Knockout (MSKO) mice in the LDL receptor knockout (LDLrKO) C57BL/6 background were developed to address this question. MSKO/LDLrKO (DKO) and LDLrKO (SKO) mice were fed chow or an atherogenic diet for 10-24wk to examine early to advanced stages of atherosclerosis. Basal (i.e. chow) plasma lipid levels were similar between genotypes, but relative to SKO mice, DKO mice had reduced plasma apoB[[Unable to Display Character: ‐]]containing lipoprotein (apoB Lp) levels throughout the diet-induced atherosclerosis progression phase resulting from decreased hepatic VLDL secretion. Despite a significant reduction in plasma apoB Lp levels, chow and atherogenic diet fed DKO mice had significantly higher cholesterol content in resident peritoneal macrophages and higher plasma proinflammatory cytokine and chemokine levels during atherogenic diet[[Unable to Display Character: ‐]]feeding compared to SKO mice. Aortic cholesterol content was similar between genotypes at early (i.e. 24wk chow-fed) or intermediate (i.e. atherogenic diet for 10wk or 16wk) stages and slightly increased at late stage atherosclerosis (i.e. 24wk atherogenic diet). Aortic root lesion area was also similar for both genotypes after 16wk of atherosclerosis induction. Transplantation of DKO or SKO BM into SKO mice followed by 16wk atherogenic diet feeding also showed similar extent of atherosclerosis. Collectively, these results suggest a novel role for myeloid cell ABCA1 in increasing hepatic VLDL secretion and plasma apoB Lp concentrations in atherogenic diet fed LDLrKO mice that offsets its atheroprotective role in decreasing macrophage cholesterol content and inflammatory response, resulting in no increase in atherosclerosis in its absence.

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Cardioprotective Effects of Diet with Different Grains on Lipid Profiles and Antioxidative System in Obesity-Induced Rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000097 ◽

2012 ◽

Vol 82 (2) ◽

pp. 85-93 ◽

Cited By ~ 9

Author(s):

Y. Kim ◽

H. Shin ◽

S. Lee

Keyword(s):

Aortic Wall ◽

Plasma Lipids ◽

Antioxidant Activities ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Thiobarbituric Acid ◽

Lipid Profiles ◽

Dietary Lipids ◽

Male Rats

In the present study, the nutritional quality of four grains including adlay (AD), buckwheat (BW), glutinous barley (GB), and white rice (WR) were evaluated in terms of plasma lipid parameters, gut transit time, and thickness of the aortic wall in rats. The rats were then raised for 4 weeks on the high-fat diet based on the American Institute of Nutrition-93 (AIN-93 G) diets containing 1 % cholesterol and 20 % dietary lipids. Forty male rats were divided into 4 groups and raised for 4 weeks with a diet containing one of the following grains: WR, AD, BW, or WB. The level of thiobarbituric acid-reactive substances (TBARS) in liver was shown to be higher in rats by the order of those fed WR, AD, GB, and BW. This indicates that other grains decreased oxidative stress in vivo more than WR. The superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase levels in the AD, BW, and GB groups were significantly higher than those in the WR group (p < 0.05). Plasma lipid profiles differed significantly according to grain combination, and decreased aortic wall thickness was consistent with the finding of decreased plasma low-density lipoprotein cholesterol (LDL-C) (p < 0.05) and increased high-density lipoprotein (HDL-C) in rats fed AD, BW, and GB (p < 0.001). The antioxidant and hypolipidemic capacities of grains are quite high, especially those of adlay, buckwheat, and glutinous barley. In conclusion, this study has demonstrated that the whole grains had a cardioprotective effect. This effect was related to several mechanisms that corresponded to lowering plasma lipids, decreasing TBARS, and increasing antioxidant activities.

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