The Novel Cholesterol-lowering Drug SR-12813 Inhibits Cholesterol Synthesis via an Increased Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

Berkhout, Theo; Simon, H.; Patel, Dilip D.; Bentzen, C.; Niesor, Eric J.; Jackson, Brian; Suckling, Keith E.

doi:10.1074/jbc.271.24.14376

Cited by 41 publications

(18 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with the observed targeting of alendronate to the osteoclast and not the osteoblast or bone marrow cells [6,8]. The decline in HMG-CoA reductase expression is consistent with earlier observations showing that the bisphosphonate SR-12813 induces degradation of HMG-CoA reductase [25], which is mediated through an unknown mechanism. The effect observed in the osteoclast appeared to be mediated, in part, by the accumulation of metabolites upstream of the BP-inhibited enzyme FPP synthase, because coadministration of simvastatin, along with alendronate, partially blocked the effect.…”

Section: Evidence For Bisphosphonate Mechanism Of Action In Vivosupporting

confidence: 92%

“…In vivo testing showed that certain compounds suppressed serum cholesterol in rodents, although alendronate had little effect [20,23], likely because of its specific targeting to bone. Other cholesterol-lowering bisphosphonates triggered degradation of hydroxymethylglutaryl coenzyme A, which is the target of the statins [24,25]. In the same context, squalene synthase inhibition by bisphosphonate was also used for the development of an assay to measure zoledronate levels in animals and clinical serum samples [26].…”

Section: Actions At the Molecular Levelmentioning

confidence: 99%

See 1 more Smart Citation

Bisphosphonate mechanism of action

2003

View full text Add to dashboard Cite

The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, this is achieved through osteoclast inhibition, which leads to reduced bone turnover, increased bone mass, and improved mineralization. The molecular targets of bisphosphonates (BPs) have recently been identified. This review will discuss the mechanism of action of BPs, focusing on alendronate and risedronate, which are the two agents most widely studied. They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation. This mechanism is responsible for N-BP suppression of osteoclastic bone resorption and reduction of bone turnover, which leads to fracture prevention.

show abstract

Section: Evidence For Bisphosphonate Mechanism Of Action In Vivosupporting

confidence: 92%

Section: Actions At the Molecular Levelmentioning

confidence: 99%

Bisphosphonate mechanism of action

2003

View full text Add to dashboard Cite

show abstract

“…In particular, the enzyme is degraded within a few hours when cells are treated with large amounts of 25-hydroxycholesterol (13,20,21). One action of this regulatory oxysterol is to rapidly increase the level of ER cholesterol (9), thereby priming HMGCoAR for homeostatic down-regulation (13).…”

Section: Resultsmentioning

confidence: 99%

How cholesterol homeostasis is regulated by plasma membrane cholesterol in excess of phospholipids

Lange

Steck

2004

Proc. Natl. Acad. Sci. U.S.A.

158

233

View full text Add to dashboard Cite

How do cells sense and control their cholesterol levels? Whereas most of the cell cholesterol is located in the plasma membrane, the effectors of its abundance are regulated by a small pool of cholesterol in the endoplasmic reticulum (ER). The size of the ER compartment responds rapidly and dramatically to small changes in plasma membrane cholesterol around the normal level. Consequently, increasing plasma membrane cholesterol in vivo from just below to just above the basal level evoked an acute (<2 h) and profound (Ϸ20-fold) decrease in ER 3-hydroxy-3-methylglutarylCoA reductase activity in vitro. We tested the hypothesis that the sharply inflected ER response to cholesterol is governed by the thermodynamic activity (fugacity) of plasma membrane cholesterol. The following two independent measures of plasma membrane cholesterol activity in human red cells and fibroblasts were used: susceptibility to cholesterol oxidase and cholesterol transfer to cyclodextrin. Both indicators revealed a threshold at the physiologic set point of plasma membrane cholesterol. Incrementing the phospholipid compartment in the plasma membrane with lysophosphatidylcholine, previously shown to decrease cholesterol oxidase susceptibility, reduced the transfer of plasma membrane cholesterol to cyclodextrin and to the ER. Conversely, the membrane intercalator, n-octanol, increased cholesterol oxidation, transfer, and ER pool size, perhaps by displacing cholesterol from plasma membrane phospholipids. We conclude that the activity of the fraction of cholesterol in excess of other plasma membrane lipids sets the cholesterol level in the ER. Cholesterol-sensitive elements therein respond by nulling the active plasma membrane pool, thereby keeping the cholesterol matched to the other plasma membrane lipids.

show abstract

“…A representative of this class of compounds, SR-12813, has been shown to inhibit the MVA pathway in HepG2 cells by increasing the rate of HMGR degradation (54). The resulting decrease in cholesterol synthesis, which was also observed in vivo in dogs that were orally administered with SR-12813, leads to hypocholesterolemia.…”

mentioning

confidence: 99%

Apomine, a Novel Hypocholesterolemic Agent, Accelerates Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase and Stimulates Low Density Lipoprotein Receptor Activity

Roitelman

Masson²,

Avner

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Apomine, a novel 1,1-bisphosphonate ester, has been shown to lower plasma cholesterol concentration in several species. Here we show that Apomine reduced the levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), the rate-limiting enzyme in the mevalonate pathway, both in rat liver and in cultured cells. Apomine resembles sterols such as 25-hydroxycholesterol in its ability to potently accelerate the rate of HMGR degradation by the ubiquitin-proteasome pathway, a process that depends on the transmembrane domain of the enzyme. The similarity between Apomine and sterols in promoting rapid HMGR degradation extends to its acute requirements for ongoing protein synthesis and mevalonate-derived non-sterol product(s) as a co-regulator. Yet, at suboptimal concentrations, sterols potentiated the effect of Apomine in stimulating HMGR degradation, indicating that these agents act via distinct modes. Furthermore, unlike sterols, Apomine inhibited the activity of acyl-CoA:cholesterol acyltransferase in intact cells but not in cell-free extracts. Apomine stimulated the cleavage of the precursor of sterolregulatory element-binding protein-2 and increased the activity of low density lipoprotein receptor pathway. This Apomine-enhanced activation of sterol-regulatory element-binding protein-2 was prevented by sterols or mevalonate. Taken together, our results provide a molecular mechanism for the hypocholesterolemic activity of Apomine.In mammalian cells, cholesterol homeostasis is maintained by balancing cholesterol uptake and production. Cholesterol uptake is regulated through modulating the levels of the cell surface low density lipoprotein (LDL) 1 receptor (LDLR), and cholesterol synthesis is regulated primarily by changes in levels and activity of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) (1, 2). HMGR is an endoplasmic reticulum (ER) enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-CoA into mevalonate (MVA), the first committed step in the MVA pathway that leads to the synthesis of cholesterol as well as of essential non-sterol isoprenoid compounds (1, 2). When cells are starved for cholesterol and/or MVA, levels of HMGR and LDLR are elevated, thus increasing the rate of endogenous sterol synthesis and of LDL uptake (3, 4). Conversely, in cholesterol-replete cells, the levels of HMGR and LDLR decline, thereby lowering sterol production and LDL internalization.HMGR and LDLR are regulated at the transcriptional level by sterol-regulatory elements (SREs) in the promoter of their genes (1, 5). Specific transcription factors, designated SREbinding proteins (SREBPs), bind to these elements and activate transcription (5, 6). The SREBP family comprises three members that control different sets of genes. SREBP-2 regulates the transcription of genes mainly involved in sterol synthesis, whereas SREBP-1a and -1c regulate principally fatty acid biosynthetic genes (7). The nuclear, transcriptionally active SREBPs are derived from the NH 2 -terminal domain of large ER membrane-bound prec...

show abstract

The Novel Cholesterol-lowering Drug SR-12813 Inhibits Cholesterol Synthesis via an Increased Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

Cited by 41 publications

References 46 publications

Bisphosphonate mechanism of action

Bisphosphonate mechanism of action

How cholesterol homeostasis is regulated by plasma membrane cholesterol in excess of phospholipids

Apomine, a Novel Hypocholesterolemic Agent, Accelerates Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase and Stimulates Low Density Lipoprotein Receptor Activity

Contact Info

Product

Resources

About