Contributions of Absorbed Dietary Cholesterol and Cholesterol Synthesized in Small Intestine to Hypercholesterolemia in Diabetic Rats

Young, Nancy L.; Lopez, Deborah; McNamara, Donald J.

doi:10.2337/diab.37.8.1151

Cited by 39 publications

(22 citation statements)

References 22 publications

(39 reference statements)

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“…It is known that cholesterol absorption is increased in chronically diabetic rats [2,3], but underlying mechanisms have remained elusive so far. Our study confirms the increased cholesterol absorption in STZ-treated rats by two independent methods.…”

Section: Discussionmentioning

confidence: 99%

“…Our data indicate that effects of insulin-deficiency on bile composition and cholesterol absorption in rats are, at least partly, attributable to changes in hepatic and intestinal Abcg5 and Abcg8 expression. [Diabetologia (2004) Type I diabetes mellitus is associated with specific changes in cholesterol metabolism in humans [1] and in experimental animals [2,3], including increased concentrations of plasma cholesterol, enhanced conversion of cholesterol into bile salts and an enhanced intestinal cholesterol absorption. The hepatobiliary pathway is of crucial importance for the maintenance of cholesterol homeostasis [4].…”

Section: Introductionmentioning

confidence: 99%

“…Type I diabetes mellitus is associated with specific changes in cholesterol metabolism in humans [1] and in experimental animals [2,3], including increased concentrations of plasma cholesterol, enhanced conversion of cholesterol into bile salts and an enhanced intestinal cholesterol absorption. The hepatobiliary pathway is of crucial importance for the maintenance of cholesterol homeostasis [4].…”

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confidence: 99%

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Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Bloks¹,

Waarde²,

Verkade³

et al. 2004

Diabetologia

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Aim/hypothesis. Type I diabetes is associated with altered hepatic bile formation and increased intestinal cholesterol absorption. The aim of this study was to evaluate whether altered expression of the ATP-Binding Cassette half-transporters Abcg5 and Abcg8, recently implicated in control of both hepatobiliary cholesterol secretion and intestinal cholesterol absorption, contributes to changed cholesterol metabolism in experimental diabetes. Methods. mRNA and protein expression of Abcg5 and Abcg8 were determined in the liver and intestine of rats with streptozotozin-induced diabetes and related to relevant metabolic parameters in plasma, liver and bile. Results. Hepatic mRNA expression of both Abcg5 (−76%) and Abcg8 (−71%) was reduced in diabetic rats when compared to control rats. In spite of increased HDL cholesterol, considered a major source of biliary cholesterol, secretion of the sterol into bile relative to that of bile salts was reduced by 65% in diabetic animals. Intestinal mRNA expression of Abcg5 (−47%) and Abcg8 (−43%) as well as Abcg5 protein contents were also reduced in insulin-deficient animals. This was accompanied by a three-to four-fold increase in plasma β-sitosterol and campesterol concentrations and by a doubling of the calculated apparent cholesterol absorption. These effects partially normalized upon insulin supplementation. Conclusion/interpretation. Our data indicate that effects of insulin-deficiency on bile composition and cholesterol absorption in rats are, at least partly, attributable to changes in hepatic and intestinal Abcg5 and Abcg8 expression. [Diabetologia (2004) Type I diabetes mellitus is associated with specific changes in cholesterol metabolism in humans [1] and in experimental animals [2,3], including increased concentrations of plasma cholesterol, enhanced conversion of cholesterol into bile salts and an enhanced intestinal cholesterol absorption. The hepatobiliary pathway is of crucial importance for the maintenance of cholesterol homeostasis [4]. Bile salts that are secreted by the liver into the intestinal lumen are required for intestinal absorption of dietary cholesterol. The majority of bile salts is subsequently reabsorbed from the intestine and returns to the liver for re-secretion into the bile. The relatively small fraction of bile salts that escapes intestinal absorption is compensated for by de novo synthesis from cholesterol in the liver. Secondly, bile contains considerable amounts of free cholesterol. Since only a part of biliary cholesterol is reabsorbed from the intestine [5], the biliary pathway contributes to a major extent to cholesterol turnover. It is well-established that

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Bloks¹,

Waarde²,

Verkade³

et al. 2004

Diabetologia

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“…23 The STZ-induced diabetes mellitus model is characterized by severe HG and is, in contrast to other diabetic animal models, not associated with reduced HDL levels. 24,25 Apo A-I gene transfer did not affect glucose or LDL cholesterol levels, 2 factors known to influence AT1R expression and reduced aortic AT1R mRNA in STZ-induced diabetic rats to levels similar to nondiabetic controls. In addition, a dose-dependent effect of HDL in attenuating HG-induced elevated AT1R expression was observed.…”

Section: Discussionmentioning

confidence: 99%

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

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Abstract-There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins.We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor (AT1R) regulation and subsequent Ang II-mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (Pϭ0.001) increase of HDL cholesterol was associated with a 4.7-fold (PϽ0.05) reduction in diabetes mellitus-induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22 phox mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (PϽ0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (PϽ0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (PϽ0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemiaϩHDLϩAng II group compared with the hyperglycemiaϩAng II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R. Diabetes mellitus is associated with endothelial dysfunction, an early phase of atherosclerosis further characterized by a reduction in NO bioavailability, without significant morphological changes of the vessel wall. 1,2 Both diabetes mellitus-associated hyperglycemia and increased angiotensin (Ang) II levels 3 induce reactive oxygen species (ROS), which contribute to endothelial dysfunction, partly via oxidative degradation of NO. Recent studies have demonstrated that ROS are predominantly produced by vascular NAD(P)H oxidase (NOX), 4 whereas "uncoupled" endothelial NO synthase (eNOS; when eNOS produces O 2 ⅐Ϫ rather then NO) is another important source of ROS in diseased, including diabetic, blood vessels. 5 Numerous studies have shown that activation of the Ang II type 1 receptor (AT1R) contributes to the induction of oxidative stress and apoptosis of vascular cells, thus contributing to the initiation and progression of endothelial dysfunction. 6 Ang II not only increases NOX activity but also uncouples eNOS in diabetic mice. 7 The expression levels of the AT1R define the biological efficacy of Ang II and have been shown to be regulated by several agonists, such as Ang II, glucose, insulin, ROS, low-density lipoprotein (LDL), and many others, 8,9 including diabetes mellitus. 10,11 The importance of the enhanced vascular AT1R expression and Ang II-mediated signaling in diabetes mellitus-associated endothelial dysfunction follows from the ...

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“…STZ-induced diabetes is characterised by a specific cholesterol metabolism [26], namely low cholesterol synthesis and high cholesterol absorption, mainly due to polyphagia and to a lesser extent to increased fractional absorption. Whereas statins are well known to reduce LDL-cholesterol and triacylglycerol and also to increase HDL-cholesterol [27], Fig.…”

Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 99%

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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Aims/hypothesis Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterollowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy. Methods Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-α, IL-1β, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/ macrophage antigen alpha, CD18/β2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferasep21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot. Results Diabetes was associated with induced cardiac stainings of TNF-α, IL-1β, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetesinduced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p<0.05) and 3.2-fold (p<0.0005), respectively, and normalised the reduced eNOS production caused by diabetes. Conclusions/interpretation These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

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Contributions of Absorbed Dietary Cholesterol and Cholesterol Synthesized in Small Intestine to Hypercholesterolemia in Diabetic Rats

Cited by 39 publications

References 22 publications

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

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