Phytosterols do not change susceptibility to obesity, insulin resistance, and diabetes induced by a high-fat diet in mice

Calpe-Berdiel, Laura; Escolà-Gil, Joan Carles; Rotllan, Noemí; Blanco‐Vaca, Francisco

doi:10.1016/j.metabol.2008.06.002

Cited by 15 publications

(8 citation statements)

References 25 publications

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“…The direct effect of stigmasterol on β-cells is unclear. While Panda and colleagues reported a decrease in serum glucose accompanied by increased circulating insulin when stigmasterol was administered to mice 36 , others have shown no effect of stigmasterol feeding on glucose tolerance 40 . Glucolipotoxicity is known to induce β-cell death and reduce β-cell function 41 .…”

Section: Oxidative Stress Increases β-Cell Cholesterolmentioning

confidence: 98%

Stigmasterol prevents glucolipotoxicity induced defects in glucose-stimulated insulin secretion

Ward

Barbosa-Lorenzi

et al. 2017

Sci Rep

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Type 2 diabetes results from defects in both insulin sensitivity and insulin secretion. Elevated cholesterol content within pancreatic β-cells has been shown to reduce β-cell function and increase β-cell apoptosis. Hyperglycemia and dyslipidemia contribute to glucolipotoxicity that leads to type 2 diabetes. Here we examined the capacity of glucolipotoxicity to induce free cholesterol accumulation in human pancreatic islets and the INS-1 insulinoma cell line. Glucolipotoxicity treatment increased free cholesterol in β-cells, which was accompanied by increased reactive oxygen species (ROS) production and decreased insulin secretion. Addition of AAPH, a free radical generator, was able to increase filipin staining indicating a link between ROS production and increased cholesterol in β-cells. We also showed the ability of stigmasterol, a common food-derived phytosterol with anti-atherosclerotic potential, to prevent the increase in both free cholesterol and ROS levels induced by glucolipotoxicity in INS-1 cells. Stigmasterol addition also inhibited early apoptosis, increased total insulin, promoted actin reorganization, and improved insulin secretion in cells exposed to glucolipotoxicity. Overall, these data indicate cholesterol accumulation as an underlying mechanism for glucolipotoxicity-induced defects in insulin secretion and stigmasterol treatment as a potential strategy to protect β-cell function during diabetes progression.

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Section: Oxidative Stress Increases β-Cell Cholesterolmentioning

confidence: 98%

Stigmasterol prevents glucolipotoxicity induced defects in glucose-stimulated insulin secretion

Ward

Barbosa-Lorenzi

et al. 2017

Sci Rep

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“…Given that the HFHC diet induces obesity and insulin resistance in C57BL/6 mice 35 and those have been associated with an impaired ability of HDL to induce cholesterol efflux, 36 we aimed to ascertain whether long-term feeding with the HFHC diet could affect fecal excretion of macrophage-derived [ 3 H]tracer. As expected, the male C57BL/6 mice gained weight rapidly (Figure 2A).…”

Section: Liver [mentioning

confidence: 99%

The Cholesterol Content of Western Diets Plays a Major Role in the Paradoxical Increase in High-Density Lipoprotein Cholesterol and Upregulates the Macrophage Reverse Cholesterol Transport Pathway

Escolà‐Gil

Llaverı́as

Julve

et al. 2011

ATVB

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Objective-A high-saturated fatty acid-and cholesterol-containing (HFHC) diet is considered to be a major risk factor for cardiovascular disease. The present study aimed to determine the effects of this Western-type diet on high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT) from macrophages to feces. Methods and Results-Experiments were carried out in mice fed a low-fat, low-cholesterol diet, an HFHC diet, or an HFHC diet without added cholesterol (high-saturated fatty acid and low-cholesterol [HFLC]). The HFHC diet caused a significant increase in plasma cholesterol, HDL cholesterol, and liver cholesterol and enhanced macrophage-derived [ 3 H]cholesterol flux to feces by 3-to 4-fold. These effects were greatly reduced in mice fed the HFLC diet. This HFHC diet-mediated induction of RCT was sex independent and was not associated with obesity or insulin resistance. The HFHC diet caused 1.4-and 3-fold increases in [ 3 H]cholesterol efflux to plasma and HDL-derived [ 3 H]tracer fecal excretion, respectively. Unlike a low-fat, low-cholesterol and HFLC diets, the HFHC diet increased liver ABCG5/G8 expression. The effect of the HFHC diet on fecal macrophage-derived [ 3 H]cholesterol excretion was totally blunted in ABCG5/G8-deficient mice. Conclusion-Despite its deleterious effects on atherosclerosis, the HFHC diet promoted a sustained compensatory macrophage-to-feces RCT. Our data provide direct evidence of the crucial role of dietary cholesterol signaling through liver ABCG5/G8 upregulation in the HFHC diet-mediated induction of macrophage-specific RCT. ietary saturated fat intake has been associated with an increased risk of atherosclerotic cardiovascular disease and metabolic diseases, such as obesity and type 2 diabetes. 1,2 This effect is thought to be mediated by an increase in plasma cholesterol, mainly low-density lipoprotein cholesterol. 3 However, both dietary saturated fat and cholesterol intake are known to raise plasma high-density lipoprotein cholesterol (HDL-C) levels. 4 -8 Several epidemiological studies and 1 meta-analysis of 60 controlled trials showed a positive correlation between high saturated fat intake and HDL-C. 9 -11 In an attempt to determine the mechanism underlying this paradoxical observation, several studies reported that a low saturated fat and cholesterol intake reduced HDL-C levels by reducing the apolipoprotein A-I secretion rate. [12][13][14] However, other studies found this effect to be associated with decreased apolipoprotein A-I fractional catabolic rates. 15,16 Also, when dietary cholesterol was increased along with total and saturated fat, increases in large high-density lipoprotein (HDL) subpopulations and HDL apolipoprotein E amounts were observed. 7,17 Macrophage-specific reverse cholesterol transport (RCT) is thought to be one of the most important HDL-mediated cardioprotective mechanisms. 18 HDL plays a critical role in cholesterol efflux from macrophages, the first step in RCT. 18 However, despite the reported changes in HDL compositi...

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“…In a few studies, plasma levels of plant sterols were inversely related to BMI and markers of insulin resistance [27]. However, phytosterol supplementation had no beneficial effect on the development of obesity and insulin resistance in a high-fat diet model of obesity in mice [28]. …”

Section: Introductionmentioning

confidence: 99%

The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease

Sabeva

Liu

Graf

2009

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review This review summarizes recent developments in the activity, regulation, and physiology of the ABCG5 ABCG8 (G5G8) transporter and the use of its xenobiotic substrates, phytosterols, as cholesterol lowering agents in the treatment of cardiovascular disease. Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome. Recent findings Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction. The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility. Finally, the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction, suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit. Summary Insulin resistance elevates G5G8 and increases susceptibility to cholesterol gallstones. However, this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine. Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease.

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Phytosterols do not change susceptibility to obesity, insulin resistance, and diabetes induced by a high-fat diet in mice

Cited by 15 publications

References 25 publications

Stigmasterol prevents glucolipotoxicity induced defects in glucose-stimulated insulin secretion

Stigmasterol prevents glucolipotoxicity induced defects in glucose-stimulated insulin secretion

The Cholesterol Content of Western Diets Plays a Major Role in the Paradoxical Increase in High-Density Lipoprotein Cholesterol and Upregulates the Macrophage Reverse Cholesterol Transport Pathway

The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease

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