Severe Atherosclerosis and Hypoalphalipoproteinemia in the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα

Mamontova, Anna G.; S, Séguret-Macé; Esposito, Bruno; Chaniale, Colette; Bouly, Muriel; Delhaye‐Bouchaud, Nicole; Luc, Gérald; Staels, Bart; Duverger, Nicolas; Mariani, Jean; Tedgui, Alain

doi:10.1161/01.cir.98.24.2738

Cited by 161 publications

(147 citation statements)

References 45 publications

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“…Intriguingly, ROR␣ has been implicated in modulating cardiovascular risks, as the ROR␣-mutant Staggerer mice are prone to lipid abnormalities and atherosclerosis (45). More recently, ROR␣ has been shown to induce the proatherothrombotic fibrinogen-␤ gene, and Staggerer mice have reduced levels of fibrinogen, which could be atheroprotective (37).…”

Section: The Pai-1 Gene Is Induced By the Constitutively Active Nuclementioning

confidence: 99%

The Orphan Nuclear Receptor Rev-erbα Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1

Wang¹,

Yin

Lazar

2006

Journal of Biological Chemistry

115

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Plasminogen activator inhibitor type 1 (PAI-1) is a major physiologic regulator of the fibrinolytic system and has recently gained recognition as a modulator of inflammation and atherosclerosis. PAI-1 exhibits circadian rhythmicity in its expression, peaking in the early morning, which is associated with increased risk for cardiovascular events. However, the mechanisms that determine PAI-1 circadian rhythmicity remain poorly understood. We discovered that the orphan nuclear receptor Reverb␣, a core component of the circadian loop, represses human PAI-1 gene expression through two Rev-erb␣ binding sites in the PAI-1 promoter. Mutations of these sites, as well as RNA interference targeting endogenous Rev-erb␣ and its corepressors, led to increased expression of the PAI-1 gene. Furthermore, glycogen synthase kinase 3␤ (GSK3␤) contributes to pai-1 repression by phosphorylating and stabilizing Rev-erb␣ protein, which can be blocked by lithium. Interestingly, serum shock generated circadian oscillations in PAI-1 mRNA in NIH3T3 cells, suggesting that PAI-1 is a direct output gene of the circadian loop. Ectopic expression of a stabilized form of Rev-erb␣ that mimics GSK3␤ phosphorylation dramatically dampened PAI-1 circadian oscillations. Thus, our results suggest that Rev-erb␣ is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction.Circadian clocks are present in cells throughout the body and drive many physiologic and disease processes. The cardiovascular system displays circadian rhythms in many of its normal functions, including platelet activation, fibrinolytic activity, and blood pressure (1), as well as in the timing of acute cardiac events such as myocardial infarction and stroke, both of which peak in the early morning (2-4). The morning excess of cardiac events may partly result from a natural circadian variation in fibrinolytic activity. Plasminogen activator inhibitor type 1 (PAI-1) 3 is a major inhibitor of fibrinolysis and exhibits a diurnal pattern in its expression (5). The morning peak of plasma PAI-1 corresponds to a nadir in net fibrinolysis, suggesting a role in the onset of acute thrombotic events (6, 7). Several lines of evidence suggest that elevated PAI-1 levels may indeed promote the development of atherothrombosis (8).Reduced fibrinolysis as result of increased plasma PAI-1 may lead directly to thrombosis and ischemia, as transgenic mice expressing a stable form of human PAI-1 develop spontaneous coronary thrombosis and myocardial infarction (9 -12). PAI-1 may also play a role in vascular remodeling and the propagation of inflammatory signals. PAI-1 interacts with the extracellular matrix protein vitronectin to inhibit endothelial cell migration, potentially compromising wound healing and neointima formation after vascular injury (13-15). Excess PAI-1 has been found in atherosclerotic plaques in humans and is further elevated in subjects with diabetes (16). PAI-1 is induced in both acute and chronic inflammatory s...

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Section: The Pai-1 Gene Is Induced By the Constitutively Active Nuclementioning

confidence: 99%

The Orphan Nuclear Receptor Rev-erbα Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1

Wang¹,

Yin

Lazar

2006

Journal of Biological Chemistry

115

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“…4 Although elevated triglycerides likely affect atherosclerosis in humans, the effect of hypertriglyceridemia in mice is modest. 69 This might explain why, despite their decreased hepatic apoC-III gene expression, 70 Rora sg/sg mice fed an atherogenic diet develop more severe atherosclerosis than wild type mice. In fact, Rora sg/sg mice show a decrease in HDL levels related to a specific reduction of apoA-I gene expression in the intestine and decreased plasma apoA-I levels, compared with wild type controls.…”

Section: Ror␣ Lipid Metabolism and Atherosclerosismentioning

confidence: 99%

“…In fact, Rora sg/sg mice show a decrease in HDL levels related to a specific reduction of apoA-I gene expression in the intestine and decreased plasma apoA-I levels, compared with wild type controls. 70 The increased susceptibility to atherosclerosis was highly correlated with the hypoalphalipoproteinemia. Interestingly, the susceptibility to atherosclerosis observed in Rora sg/sg fed an atherogenic diet resembles the exacerbated atherosclerosis development in female apoA-I-deficient mice crossed with human apoB transgenic mice and fed a high fat diet to increase total and LDL cholesterol.…”

Section: Ror␣ Lipid Metabolism and Atherosclerosismentioning

confidence: 99%

The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

ATVB

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Abstract-Retinoic acid receptor-related Orphan Receptor ␣ (ROR␣) is a member of the nuclear hormone receptor superfamily. ROR␣ has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of ROR␣. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of ROR␣ activity. The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, ROR␣ appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making ROR␣ an intracellular cholesterol target. Key Words: ROR␣ Ⅲ cholesterol Ⅲ statins Ⅲ atherosclerosis Ⅲ lipid homeostasis R etinoic acid receptor-related Orphan Receptor ␣ (ROR␣), initially described as an orphan nuclear receptor, has recently been deorphanized by the identification of its natural ligand as cholesterol or a cholesterol derivative. 1,2 ROR␣ has been shown to be implicated in the development and/or differentiation of many tissues, and provides protection against age-related degenerative processes, including atherosclerosis. In addition, ROR␣ activates the apolipoprotein A-I (apoA-I) and apoC-III gene transcription, 3,4 modulates the vasomotor tone of small resistance arteries, and participates in the regulation of postischemic angiogenesis. 5,6 This review focuses on the link between ROR␣, vascular biology, and cholesterol homeostasis. Interestingly, recent findings suggest that ROR␣ is an intracellular cholesterol target. 1

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“…Homozygous sg/sg mice have a lean and dyslipidemic phenotype. Several studies on Ror␣ (16,19,23,32,33,39) have revealed a role for this nuclear receptor in fatty acid homeostasis. These mice display hypoalphalipoproteinemia, decreased serum triacylglycerol and HDL cholesterol, and vulnerability to atherosclerosis (23).…”

mentioning

confidence: 99%

“…Several studies on Ror␣ (16,19,23,32,33,39) have revealed a role for this nuclear receptor in fatty acid homeostasis. These mice display hypoalphalipoproteinemia, decreased serum triacylglycerol and HDL cholesterol, and vulnerability to atherosclerosis (23). Furthermore, sg/sg mice display reduced adiposity, increased metabolic rate, improved insulin sensitivity, resistance to diet-induced obesity, and hepatic steatosis (17,18).…”

mentioning

confidence: 99%

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

Lau

Tuong

Wang

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue. Am J Physiol Endocrinol Metab 308: E159-E171, 2015. First published November 25, 2014; doi:10.1152/ajpendo.00056.2014.-The Rarrelated orphan receptor-␣ (Ror␣) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Ror␣-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Ror␣-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Ppar␣, Err␣, Dio2, Acot11/Bfit, Cpt1␤, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesityresistant phenotype in Ror␣-deficient mice.retinoic acid receptor-related orphan receptor-␣; obesity; adiposity; adipose tissue; uncoupling protein-1 OBESITY IS A METABOLIC DISEASE that affects more than 10% of the global population. Energy imbalance as a result of excess dietary energy intake or genetic susceptibility results in increased energy storage and adiposity. Current strategies to ameliorate this disease include increasing energy expenditure through physical exercise and reducing energy consumption. However, the success rate is limited by compliance and the genetic disposition to maintain energy balance.Adaptive thermogenesis is an adrenergic/sympathetic-dependent mechanism utilized by mammals to increase energy expenditure in response to excessive dietary intake and/or cold stimulus. Thermogenesis occurs in both brown adipose tissue and beige fat [white adipose tissue cells that acquire a brown adipose phenotype (37, 41)]. This process involves increased (fatty acid-dependent) expression and activity of the thermogenic mitochondrial uncoupling protein (Ucp1). The function of Ucp1 is to me...

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Severe Atherosclerosis and Hypoalphalipoproteinemia in the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα

Cited by 161 publications

References 45 publications

The Orphan Nuclear Receptor Rev-erbα Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1

The Orphan Nuclear Receptor Rev-erbα Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1

The “CholesteROR” Protective Pathway in the Vascular System

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

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