Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation

Umemoto, Takuya; Subramanian, Savitha; Ding, Yiwen; Goodspeed, Leela; Wang, Shari; Han, Chang Yeop; Teresa, Antonio Sta.; Kim, Jinkyu; O’Brien, Kevin D.; Chait, Alan

doi:10.1194/jlr.m029264

Cited by 23 publications

(23 citation statements)

References 46 publications

(68 reference statements)

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“…The interactions between oxidized chylomicron remnants and endothelial cells were reported to be deleterious to endothelial cell function measured by carbacholine-mediated vasorelaxation (8). At least one other recent study confirmed that addition of cholesterol to the diet only contributes marginally to the total circulating amount of cholesterol but has important effects for atherosclerotic plaque formation and that blocking intestinal cholesterol absorption could alleviate these effects (11,28). This could explain why cholesterol derived specifically from dietary origin can have such important vascular consequences, even before plaque formation is visible.…”

Section: Discussionmentioning

confidence: 68%

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

Laplante

Charbonneau

Avramoglu

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Section: Discussionmentioning

confidence: 68%

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

Laplante

Charbonneau

Avramoglu

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Mass spectrometry: Acyl carnitines and ceramides were quantified by liquid chromatography-electron spray ionization-tandem mass spectrometry (LC/ESI-MS/MS) in the multiple reaction monitoring (MRM) mode as previously described (Kasumov et al, 2010; Umemoto et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor

et al. 2016

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Summary Histone deacetylase 3 (HDAC3), a chromatin modifying enzyme, requires association with the deacetylase containing domain (DAD) of the nuclear receptor co-repressors NCOR1 and SMRT for its stability and activity. Here we show that aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, competes with HDAC3 to bind the NCOR1/SMRT DAD. Increased AR expression leads to HDAC3 degradation followed by increased PPARγ signaling resulting in lipid accumulation in the heart. AR also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, thus affecting activity of the nuclear corepressor complex itself. Though AR reduces HDAC3-corepressor complex formation, it specifically de-represses the retinoic acid receptor (RAR), but not other nuclear receptors such as the thyroid receptor (TR) and liver X receptor (LXR). In summary, this work defines a distinct role for AR in lipid and retinoid metabolism through HDAC3 regulation and consequent de-repression of PPARγ and RAR.

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“…11 In the LDLR model challenged with a high-cholesterol diabetogenic diet, EZ reduced hepatic steatosis but not other obesity phenotypes such as adipose tissue inflammation. 12 EZ was shown to produce a modest, but significant, reduction in hepatic fat and liver enzymes in a Japanese population of patients with NAFLD. 13 In addition, a recent clinical trial suggests that EZ may improve measures of insulin resistance in diabetic insulin-resistant subjects.…”

mentioning

confidence: 95%

Acceleration of Biliary Cholesterol Secretion Restores Glycemic Control and Alleviates Hypertriglyceridemia in Obese db / db Mice

Shu

Sabeva

Wang

et al. 2014

ATVB

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Objective Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice. Approach and Results Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period. Conclusions Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.

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Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation

Cited by 23 publications

References 46 publications

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor

Acceleration of Biliary Cholesterol Secretion Restores Glycemic Control and Alleviates Hypertriglyceridemia in Obese db / db Mice

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