Regulatory Adaptation of Isoprenoid Biosynthesis and the LDL Receptor Pathway in Fibroblasts from Patients with Mevalonate Kinase Deficiency

Gf, Hoffmann; Un, Wiesmann; Brendel, Susanne; Rk, Keller; Gibson, Kevin J.

doi:10.1203/00006450-199704000-00014

Cited by 22 publications

(17 citation statements)

References 19 publications

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“…These patients are characterized by mevalonic aciduria and a broad range of phenotypic findings, including malformations of the central nervous system, facial dysmorphy, psychomotor retardation, and recurrent fever episodes. Plasma cholesterol levels are normal in subjects with mevalonate kinase deficiency, suggesting that compensatory mechanisms, such as increased activities of HMG-CoA reductase and the LDL receptor pathway (50), are sufficient to overcome the enzyme deficiency and provide adequate synthesis of cholesterol as well as non-sterol intermediates for embryogenesis.…”

Section: Discussionmentioning

confidence: 99%

Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene

Ohashi

Osuga

Tozawa

et al. 2003

Journal of Biological Chemistry

103

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The endoplasmic reticulum (ER) enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate, catalyzes the ratelimiting step in cholesterol biosynthesis. Because this mevalonate pathway also produces several non-sterol isoprenoid compounds, the level of HMG-CoA reductase activity may coordinate many cellular processes and functions. We used gene targeting to knock out the mouse HMG-CoA reductase gene. The heterozygous mutant mice (Hmgcr؉/؊) appeared normal in their development and gross anatomy and were fertile. Although HMG-CoA reductase activities were reduced in Hmgcr؉/؊ embryonic fibroblasts, the enzyme activities and cholesterol biosynthesis remained unaffected in the liver from Hmgcr؉/؊ mice, suggesting that the haploid amount of Hmgcr gene is not rate-limiting in the hepatic cholesterol homeostasis. Consistently, plasma lipoprotein profiles were similar between Hmgcr؉/؊ and Hmgcr؉/؉ mice. In contrast, the embryos homozygous for the Hmgcr mutant allele were recovered at the blastocyst stage, but not at E8.5, indicating that HMG-CoA reductase is crucial for early development of the mouse embryos. The lethal phenotype was not completely rescued by supplementing the dams with mevalonate. Although it has been postulated that a second, peroxisome-specific HMG-CoA reductase could substitute for the ER reductase in vitro, we speculate that the putative peroxisomal reductase gene, if existed, does not fully compensate for the lack of the ER enzyme at least in embryogenesis.The mevalonate pathway produces isoprenoids that are essential for diverse cellular functions, ranging from cholesterol synthesis to growth control. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) 1 reductase (EC 1.1.1.34), which catalyzes the conversion of HMG-CoA to mevalonate, is the rate-limiting enzyme in the mevalonate pathway (1). Because of its major role in cholesterol biosynthesis, the regulation of HMG-CoA reductase has been intensely studied. To ensure a steady mevalonate supply, the non-sterol and sterol end-products of mevalonate metabolism exert feedback regulation on the activity of this enzyme through multivalent mechanisms, including inhibition of transcription of the HMG-CoA reductase mRNA, blocking of translation, and acceleration of protein degradation, thus regulating the amount of reductase protein over a several hundred-fold range (reviewed in Refs.

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Section: Discussionmentioning

confidence: 99%

Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene

Ohashi

Osuga

Tozawa

et al. 2003

Journal of Biological Chemistry

103

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“…Thus, it appears that MA fibroblasts are able to compensate for their defect in MK and that the flux through the cholesterol biosynthesis pathway may be rather normal. This is due to increased activity of HMG-CoA reductase and the LDL receptor pathway in such cells (19,20). It has been reported that this increased activity of HMG-CoA reductase is insuppressible by exogenous LDL cholesterol and can be up-regulated further under cholesterol-free culture conditions (19).…”

mentioning

confidence: 99%

Regulation of Isoprenoid/Cholesterol Biosynthesis in Cells from Mevalonate Kinase-deficient Patients

Houten

Schneiders

Wanders

et al. 2003

Journal of Biological Chemistry

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Mevalonic aciduria (MA) and hyper-IgD and periodic fever syndrome (HIDS) are two inherited disorders both caused by depressed mevalonate kinase (MK) activity. MK is the first enzyme to follow the highly regulated 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), which catalyzes the rate-limiting step in the isoprenoid/cholesterol biosynthesis pathway. In fibroblasts of MA patients, but not of HIDS patients, HMGR activity is elevated under normal growth conditions. This activity is down-regulated when cells are supplemented with the isoprenoid precursors geraniol, farnesol, and geranylgeraniol, and a mixture of 25-hydroxycholesterol and cholesterol. This indicates that the regulation of the pathway in these cells is not disturbed. The elevated HMGR activity is probably due to a shortage of non-sterol isoprenoid end products, as indicated by normal HMGR mRNA levels in MA fibroblasts. Furthermore, the HMGR activity in MA cells was more sensitive to geranylgeraniol suppression and less sensitive to sterol suppression than the HMGR activity in low density lipoprotein receptor-deficient cells. HMGR activity in MA cells was down-regulated also by addition of its product mevalonate to the culture medium. Thus, it appears that the elevation of mevalonate levels, which are high in MA patients and moderate in HIDS patients, allows the cells to compensate for the depressed MK activity. Indeed, the isoprenylation of Ras and RhoA protein appeared normal in HIDS and MA fibroblasts under normal conditions but showed increased sensitivity toward inhibition of HMGR by simvastatin. Our results indicate that MK-deficient cells maintain the flux through the isoprenoid/cholesterol biosynthesis pathway by elevating intracellular mevalonate levels.

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“…Intriguingly, MK enzyme activity appears to be sensitive to temperature, with lower enzyme activity measured in vitro when cells are incubated at higher temperatures (73). There is no absolute deficiency of any of the isoprenoid end-products, although in mevalonic aciduria there is a slight decrease in cholesterol, dolichol, and ubiquinone-10 (72,74,78,80). The mutated MK still responds to feedback regulation by SREBPs (97,126).…”

Section: Review Of Pathophysiology Per Syndromementioning

confidence: 92%

Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes

Simon¹,

Meer²

2007

American Journal of Physiology-Regulatory, Integrative and Comp

131

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Familial periodic fever syndromes, otherwise known as hereditary autoinflammatory syndromes, are inherited disorders characterized by recurrent episodes of fever and inflammation. The general hypothesis is that the innate immune response in these patients is wrongly tuned, being either too sensitive to very minor stimuli or turned off too late. The genetic background of the major familial periodic fever syndromes has been unraveled, and through research into the pathophysiology, a clearer picture of the innate immune system is emerging. After an introduction on fever, interleukin-1beta and inflammasomes, which are involved in the majority of these diseases, this manuscript offers a detailed review of the pathophysiology of the cryopyrin-associated periodic syndromes, familial Mediterranean fever, the syndrome of pyogenic arthritis, pyoderma gangrenosum and acne, Blau syndrome, TNF-receptor-associated periodic syndrome and hyper-IgD and periodic fever syndrome. Despite recent major advances, there are still many questions to be answered regarding the pathogenesis of these disorders.

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Regulatory Adaptation of Isoprenoid Biosynthesis and the LDL Receptor Pathway in Fibroblasts from Patients with Mevalonate Kinase Deficiency

Cited by 22 publications

References 19 publications

Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene

Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene

Regulation of Isoprenoid/Cholesterol Biosynthesis in Cells from Mevalonate Kinase-deficient Patients

Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes

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