Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice

Macdonald, M. L. E.; Singaraja, Roshni R.; Bissada, Nagat; Ruddle, Piers; Watts, Russell; Karasinska, Joanna M.; Gibson, William T.; Fiévet, Catherine; Vance, Jean E.; Staels, Bart; Hayden, Michael R.

doi:10.1194/jlr.m700478-jlr200

Cited by 62 publications

(59 citation statements)

References 96 publications

(100 reference statements)

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“…14). Deletion of scd1 gene reduces the development of metabolic syndrome (reduces plasma TG, reduces weight gain, and increases insulin sensitivity) in severely hyperlipidemic low-density lipoprotein receptor-deficient mice fed a Western diet (30). Both laminar shear stress and the PPAR␥ agonists, troglitazone and rosiglitazone, increased the gene expression of scd1 in endothelial cells (38).…”

Section: Discussionmentioning

confidence: 99%

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

Simeone

Li²,

Paradis³

et al. 2011

Physiological Genomics

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Simeone SM, Li MW, Paradis P, Schiffrin EL. Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium. Physiol Genomics 43: 148 -160, 2011. First published November 2, 2010; doi:10.1152/physiolgenomics.00218.2009.-Endothelin (ET)-1 plays an important pathophysiological role in several vascular diseases including hypertension and atherosclerosis. Transgenic mice overexpressing human preproET-1 selectively in the endothelium (eET-1) exhibit vascular injury in the absence of blood pressure elevation. ET-1 overexpression may induce vascular injury by inducing changes in gene expression. To understand mechanisms whereby ET-1 induces vascular damage, vascular gene expression profiling was performed using DNA microarrays. RNA from mesenteric arteries of male and female young (6 -7 wk) and mature (6 -8 mo) eET-1 and wild-type (WT) mice was isolated, and changes in gene expression were determined by genome-wide expression profiling using Illumina microarray and FlexArray software. Data were analyzed using a relaxed and a stringent statistical approach. The gene lists were compared and analyzed as well with Ingenuity Pathway Analysis. The most common change was an increase in the expression of lipid metabolism genes. Four of these genes were validated by qPCR, cyp51, dgat2, and scd1 genes in young and elovl6 in both young and mature male mice, supporting a role of ET-1 in atherosclerosis. To test the hypothesis that ET-1 participates in mechanisms leading to atherosclerosis, we crossed eET-1 with atherosclerosisprone apoE Ϫ/Ϫ mice to determine whether ET-1 overexpression exacerbates high-fat diet (HFD)-induced atherosclerosis using oil red O staining of descending thoracic aorta. HFD increased lipid plaques by 3-, 27-, and 86-fold in eET-1, apoE Ϫ/Ϫ , and crossed mice, respectively, vs. WT. This suggests that increased endothelial ET-1 expression results in early changes in gene expression in the vascular wall that enhance lipid biosynthesis and accelerate progression of atherosclerosis. aorta; artery; lipid biosynthesis; vascular remodeling; inflammation; atherosclerosis ESSENTIAL HYPERTENSION IS characterized by increased peripheral resistance to blood flow (48). The vasoconstrictor peptide endothelin-1 (ET-1) (58), which has a critical role in normal development and probably in regulation of blood flow in normal physiology (24), has been associated with increased blood pressure (BP) in human and experimental animal studies (1, 47). ET-1 has also been implicated in other pathophysiological conditions such as pulmonary hypertension (16), atherosclerosis (4, 22, 56), heart failure (17,19,35,46,52), myocardial infarction (8, 34), and chronic renal failure (1, 11, 37), among others (49). ET-1 is produced predominantly by endothelial cells but also by many other cells and tissues such as vascular smooth muscle cells, fibroblasts, macrophages/ monocytes and cardiomyocytes, as well as noncardiovascular cells and tissues such as renal tubular epithelial cells, glial cells, and pituitary cell...

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Section: Discussionmentioning

confidence: 99%

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

Simeone

Li²,

Paradis³

et al. 2011

Physiological Genomics

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“…[16,23] In fact, the inhibition of SCD-1 seems to prevent diet-induced obesity, NAFLD, glucose tolerance, and insulin intolerance in rodents. [21,22] Consequently, inhibitors of SCD-1 have been proposed for the treatment of obesity and metabolic diseases. [16] Palmitoleic acid has been described as a powerful blocker (of activity and expression) of SCD-1, reducing insulin resistance and NAFLD in mice.…”

Section: Palmitoleic Acid and The Role Of Scd In Metabolic Diseasementioning

confidence: 99%

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders?

Souza

Vannice²,

Neto

et al. 2017

Molecular Nutrition Food Res

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Although dietary fatty acids can modulate metabolic and immune responses, the effects of palmitoleic acid (16:1n-7) remain unclear. Since this monounsaturated fatty acid is described as a lipokine, studies with cell culture and rodent models have suggested it enhances whole body insulin sensitivity, stimulates insulin secretion by β cells, increases hepatic fatty acid oxidation, improves the blood lipid profile, and alters macrophage differentiation. However, human studies report elevated blood levels of palmitoleic acid in people with obesity and metabolic syndrome. These findings might be reflection of the level or activity of stearoyl-CoA desaturase-1, which synthesizes palmitoleate and is enhanced in liver and adipose tissue of obese patients. The aim of this review is to describe the immune-metabolic effects of palmitoleic acid observed in cell culture, animal models, and humans to answer the question of whether palmitoleic acid is a plausible nonpharmacological strategy to prevent, control, or ameliorate chronic metabolic and inflammatory disorders. Despite the beneficial effects observed in cell culture and in animal studies, there are insufficient human intervention studies to fully understand the physiological effects of palmitoleic acid. Therefore, more human-based research is needed to identify whether palmitoleic acid meets the promising therapeutic potential suggested by the preclinical research.

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“…8 Absence of SCD1 reduces hepatic steatosis and plasma TG (by Ϸ50%) and provides striking protection from diet-induced weight gain and insulin resistance in LDLRdeficient mice. 7 A major unanswered question is whether the amelioration of these features in SCD1-deficient mice will lead to reduced susceptibility to atherosclerosis.…”

mentioning

confidence: 99%

“…4 SCD1-deficient mice are protected from insulin resistance and diet-induced obesity 5 and have a markedly reduced rate of VLDL-TG production. 6 We have recently shown 7 that SCD1 deficiency improves the metabolic phenotype of a hyperlipidemic LDLR-deficient mouse model of familial hypercholesterolemia (FH). 8 On a Western diet, LDLR-deficient mice develop diet-induced diabetes and obesity and develop atherosclerosis over 2 to 3 months.…”

mentioning

confidence: 99%

Despite Antiatherogenic Metabolic Characteristics, SCD1-Deficient Mice Have Increased Inflammation and Atherosclerosis

Macdonald

Eck

Hildebrand

et al. 2009

ATVB

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Objective-Absence of stearoyl-CoA desaturase-1 (SCD1) in mice reduces plasma triglycerides and provides protection from obesity and insulin resistance, which would be predicted to be associated with reduced susceptibility to atherosclerosis. The aim of this study was to determine the effect of SCD1 deficiency on atherosclerosis. Methods and Results-Despite an antiatherogenic metabolic profile, SCD1 deficiency increases atherosclerosis in hyperlipidemic low-density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Lesion area at the aortic root is significantly increased in males and females in two models of SCD1 deficiency. Inflammatory changes are evident in the skin of these mice, including increased intercellular adhesion molecule (ICAM)-1 and ulcerative dermatitis. Increases in ICAM-1 and interleukin-6 are also evident in plasma of SCD1-deficient mice. HDL particles demonstrate changes associated with inflammation, including decreased plasma apoA-II and apoA-I and paraoxonase-1 and increased plasma serum amyloid A. Lipopolysaccharide-induced inflammatory response and cholesterol efflux are not altered in SCD1-deficient macrophages. In addition, when SCD1 deficiency is limited to bone marrow-derived cells, lesion size is not altered in LDLR-deficient mice. Oleic acid is the major fatty acid found in triglycerides (TG) and cholesteryl esters (CE), 2 likely because of its status as the preferred fatty acid substrate of acyl-CoA:cholesterol acyltransferase (ACAT), 3 and the close proximity of SCD to diacylglycerol acyltransferase-2 in the endoplasmic reticulum (ER). 4 SCD1-deficient mice are protected from insulin resistance and diet-induced obesity 5 and have a markedly reduced rate of VLDL-TG production. 6 We have recently shown 7 that SCD1 deficiency improves the metabolic phenotype of a hyperlipidemic LDLR-deficient mouse model of familial hypercholesterolemia (FH). 8 On a Western diet, LDLR-deficient mice develop diet-induced diabetes and obesity and develop atherosclerosis over 2 to 3 months. 8 Absence of SCD1 reduces hepatic steatosis and plasma TG (by Ϸ50%) and provides striking protection from diet-induced weight gain and insulin resistance in LDLRdeficient mice. 7 A major unanswered question is whether the amelioration of these features in SCD1-deficient mice will lead to reduced susceptibility to atherosclerosis. Conclusions-TheseIn this study, we show that despite these antiatherogenic metabolic characteristics, SCD1 deficiency surprisingly increases lesion size in hyperlipidemic LDLR-deficient mice and that this acceleration in atherosclerosis is likely to result from chronic inflammation primarily of the skin, which then leads to changes in markers of inflammation in plasma and proinflammatory changes in HDL. ϩ/ϩ Ldlr Ϫ/Ϫ mice that were not littermates (Ϸ63% of all animals studied). Mice deficient in SCD1 with the Scd1 ab-J allele were used in all experiments except those involving analysis of atherosclerotic lesions and paraoxonase-1 (PON1) activity, in which mice carryin...

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Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice

Cited by 62 publications

References 96 publications

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders?

Despite Antiatherogenic Metabolic Characteristics, SCD1-Deficient Mice Have Increased Inflammation and Atherosclerosis

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