Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate. We devised a simple, non-invasive method for collecting 24-h urine in our subjects. With a background of a very low cholesterol diet, mean mevalonate excretion did not differ between controls and SLOS children, indicating that SLOS subjects have normal HMGCoA reductase activity. In a short term feeding study, the effects of a high cholesterol diet in SLOS subjects include a significant 55% increase in plasma cholesterol levels and 39% decrease in mevalonate excretion and no change in plasma 7-DHC levels. However, in four SLOS subjects, fed a high cholesterol diet for 2-3 years, plasma cholesterol levels continued to increase, urinary mevalonate excretion remained low and total 7-DHC decreased significantly, likely from decreased total sterol synthesis.Thus, in SLOS subjects, HMG-CoA reductase activity was normal and was subject to normal cholesterol induced feedback inhibition. However, total sterol synthesis in SLOS may still be decreased because of increased diversion of mevalonate into the shunt pathway away from sterol synthesis. -

Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol

“…All dietary studies were carried out precisely as described in our earlier studies (7). The high-cholesterol diets consisted of the very low-cholesterol diet supplemented with hard-boiled egg yolk or crystalline cholesterol.…”

“…Twenty-four hour urine was collected using preweighed cotton diapers from infants and children with SLOS with physical limitations, according to the procedure reported previously (7). From toilet-trained children, 24 h urine was collected.…”

“…Studies in our laboratory have shown that urinary mevalonate excretion in SLOS children maintained on a very low-cholesterol diet is comparable with that observed in control children given the same diet. Mevalonate excretion is subject to sustained reduction when dietary cholesterol is increased (7). Thus, children with SLOS, who have low cholesterol levels, exhibit normal baseline HMG-CoA reductase activity and normal feedback inhibition by dietary cholesterol.…”

“…Children with Smith-Lemli-Opitz syndrome (SLOS) have a defect in the cholesterol biosynthetic pathway at the step of sterol-D 7 -reductase (EC 1.3.1.21), which converts 7-dehydrocholesterol (7-DHC) to cholesterol, resulting in increased levels of 7-DHC and low levels of cholesterol in plasma and tissues (1)(2)(3). The clinical manifestations of this inherited autosomal recessive metabolic syndrome include severe growth deficiency and congenital malformations as well as endocrine and neurological dysfunction, including in most cases mental retardation (4).…”

Nutrition Research and the Impact of Computational Systems Biology

“…Secondly, nutrient-based biochemical systems contain diverse components that give rise to overlapping metabolic networks, comprising of numerous interactions [8][9][10]. Many of these interactions are non-linear in nature and can involve complex feedback and feed-forward loops [11][12][13]. Thus, it is challenging and even unfeasible to reason about these by human intuition alone.…”