Role of cholesterol in embryonic development

Abstract

We showed previously that 3 distal inhibitors of cholesterol synthesis are highly teratogenic in rats. AY 9944 and BM 15766 inhibit 7-dehydrocholesterol reductase, which catalyzes the last step of cholesterol synthesis, and triparanol inhibits Delta(24)-dehydrocholesterol reductase, which catalyzes the last step in another pathway. These molecules cause holoprosencephalic brain anomalies. Under certain experimental conditions, other anomalies (of the limbs and male genitalia) are also observed. Assays performed by gas chromatography-mass spectrometry (GC-MS) show hypocholesterolemia and an accumulation of precursors. These data indicate that this animal model can be considered a model of Smith-Lemli-Opitz syndrome. Smith-Lemli-Opitz syndrome is a recessive autosomal genetic disease characterized by malformations (microcephaly, corpus callosum agenesis, holoprosencephaly, and mental retardation), male pseudohermaphroditism, finger anomalies, and failure to thrive. The syndrome has been attributed to a deficit in 7-dehydrocholesterol reductase. As assayed by GC-MS, the sterol status of these patients indicates severe hypocholesterolemia and an accumulation of precursors: 7-dehydrocholesterol, 8-dehydrocholesterol, and oxidized derivatives. The presence of 7-dehydrocholesterol in the serum of patients is pathognomonic of the disease. The developmental gene Shh (sonic hedgehog) plays a key role in brain, limb, and genital development; it was shown recently that the Shh protein has to be covalently linked to cholesterol to be active. This is the first time that a posttranslational function has been attributed to cholesterol. There is an obvious relation between Shh dysfunction and the malformations observed in our experiments and in patients with Smith-Lemli-Opitz syndrome. However, the exact relation remains to be clarified. It is clear, however, that the role of cholesterol in embryonic development must be taken into account.

Hypocholesterolemia in Clinically Serious Conditions - Review

“…This gene is responsible for the proper development of tissues and for the organization of embryonic tissue. SHH regulating protein must bind to cholesterol to be active 93 . Hypocholesterolemia is also related to decreases in some plasma proteins.…”

Cholesterol oxidation: Health hazard and the role of antioxidants in prevention

“…Cholesterol also provides the structural scaffolding for the synthesis of steroids a n d s t e r o i d h o r m o n e s , a n d f o r t h e biosynthesis of bile and bile acid salts. Sterol plays also an important role in embryonic development (Roux et al, 2000). …”

Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

“…Furthermore, the highest expression of Xdhcr7 was detected by RT-PCR analysis from early gastrulation to early organogenesis stages, a time-window during which different tissue and organ identities are established. The general role of cholesterol in embryonic development is well described (Wolf, 1999;Moebius et al, 2000;Roux et al, 2000;Kelley and Herman, 2001). The early expression of Xdhcr7 is in accordance with the multiple developmental defects reported in DHCR7 mutations (Porter, 2000;Waterham and Wanders, 2000;Nowaczyk and Waye, 2001;WitschBaumgartner et al, 2001;Ciara et al, 2004), since the reported phenotypes may result from a failure of early patterning events.…”

“…It is interesting to note that recently a connection between Hedgehog signaling and the PCP pathway has been elucidated in Xenopus (Park et al, 2006). In fact, with regard to the wide spectrum of functions fulfilled by cholesterol in vertebrates (Wolf, 1999;Incardona and Eaton, 2000;Roux et al, 2000;Herz and Bock, 2002;Pfrieger, 2003a,c), a perturbation of cholesterol biosynthesis is likely to affect multiple cellular processes, among which Hh signalling may be one of the most sensitive.…”