Genetic Disorders of Cholesterol Biosynthesis in Mice and Humans

Nwokoro, Ngozi A.; Wassif, Christopher A.; Porter, Forbes D.

doi:10.1006/mgme.2001.3226

Cited by 66 publications

(41 citation statements)

References 100 publications

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“…On the other hand, cholesterol is the precursor of many steroids, and inborn errors of cholesterol synthesis are associated with malformation syndromes, 18,19 such as SmithLemli-Optiz Syndrome (SLOS) or holoprosencephaly. Cholesterol is required during the posttranslational modification of Sonic hedgehog (Shh): cholesterol must be covalently attached to the N-terminal component of the protein 20 to allow its auto-cleavage and its morphogenic function.…”

Section: Cellular Roles Of Cholesterolmentioning

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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Section: Cellular Roles Of Cholesterolmentioning

confidence: 99%

The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

ATVB

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“…At least 8 human malformation syndromes are caused by inherited enzyme defects in this pathway (1)(2)(3)(4). Five of these human defects have mouse counterparts that arose through random mutagenesis or were generated by targeted recombination.…”

Section: Introductionmentioning

confidence: 99%

Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin

Engelking¹,

Evers²,

Richardson³

et al. 2006

J. Clin. Invest.

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Insig-1 and Insig-2 are regulatory proteins that restrict the cholesterol biosynthetic pathway by preventing proteolytic activation of SREBPs and by enhancing degradation of HMG-CoA reductase. Here, we created Insig-double-knockout (Insig-DKO) mice that are homozygous for null mutations in Insig-1 and Insig-2. After 18.5 days of development, 96% of Insig-DKO embryos had defects in midline facial development, ranging from cleft palate (52%) to complete cleft face (44%). Middle and inner ear structures were abnormal, but teeth and skeletons were normal. The animals were lethargic and runted; they died within 1 day of birth. The livers and heads of Insig-DKO embryos overproduced sterols, causing a marked buildup of sterol intermediates. Treatment of pregnant mice with the HMG-CoA reductase inhibitor lovastatin reduced sterol synthesis in Insig-DKO embryos and reduced the pre-cholesterol intermediates. This treatment ameliorated the clefting syndrome so that 54% of Insig-DKO mice had normal faces, and only 7% had cleft faces. We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice. These findings have implications for the pathogenesis of the cleft palate component of Smith-Lemli-Opitz syndrome and other human malformation syndromes in which mutations in enzymes catalyzing steps in cholesterol biosynthesis produce a buildup of sterol intermediates.

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“…The necessity of synthesized cholesterol by the fetus and/or embryo is depicted best by fetuses and/or embryos unable to synthesize cholesterol. There are 7 known defects in the sterol biosynthetic pathway, all of which will lead to congenital malformations [1][2][3]. The most common of the defects is the Smith-Lemli-Opitz syndrome (SLOS).…”

Section: Introductionmentioning

confidence: 99%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SUMMARYThe requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2-to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.

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Genetic Disorders of Cholesterol Biosynthesis in Mice and Humans

Cited by 66 publications

References 100 publications

The “CholesteROR” Protective Pathway in the Vascular System

The “CholesteROR” Protective Pathway in the Vascular System

Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

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