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the 3rd letter of the Roman alphabet (同)c
(music) the keynote of the scale of C major
a general-purpose programing language closely associated with the UNIX operating system
the 8th letter of the Roman alphabet (同)h
an enzyme that catalyses the biochemical reduction of some specified substance

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carbonの化学記号
hydrogenの化学記号
鉛筆の硬度 / 《俗》heroin
cobaltの化学記号

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2018/04/16 19:24:44」(JST)

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hydroxymethylglutaryl-CoA reductase

Identifiers

EC number

1.1.1.34

Databases

IntEnz

IntEnz view

BRENDA

BRENDA entry

ExPASy

NiceZyme view

KEGG

KEGG entry

MetaCyc

metabolic pathway

PRIAM

profile

PDB structures

RCSB PDB PDBe PDBsum

Search
PMC	articles
PubMed	articles
NCBI	proteins

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, which is considered, by those who accept the standard lipid hypothesis, an important determinant of atherosclerosis.^[5] This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins.

HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum, and was long regarded as having seven transmembrane domains, with the active site located in a long carboxyl terminal domain in the cytosol. More recent evidence shows it to contain eight transmembrane domains.^[6]

In humans, the gene for HMG-CoA reductase is located on the long arm of the fifth chromosome (5q13.3-14).^[7] Related enzymes having the same function are also present in other animals, plants and bacteria.

1 Structure
2 Function
- 2.1 Interactive pathway map
3 Inhibitors
- 3.1 Drugs
- 3.2 Hormones
4 Clinical significance
5 Regulation
- 5.1 Transcription of the reductase gene
- 5.2 Translation of mRNA
- 5.3 Degradation of reductase
- 5.4 Phosphorylation of reductase
6 See also
7 References
8 Further reading
9 External links

Structure

The main isoform (isoform 1) of HMG-CoA reductase in humans is 888 amino acids long. It is a polytopic transmembrane protein (meaning it possesses many alpha helical transmembrane segments). It contains two main domains:

an N-terminal sterol-sensing domain (amino acid interval: 88-218), which binds sterol groups. Cholesterol binding at this region inhibits the activity of the catalytic domain.
a C-terminal catalytic domain (amino acid interval: 489-871), namely the 3-hydroxy-3-methyl-glutaryl-CoA reductase domain. This domain is required for the proper enzymatic activity of the protein.

Isoform 2 is 835 amino acids long. This variant is shorter because it lacks an exon in the middle region. This does not affect any of the aforementioned domains.

Function

HMGCR catalyses the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol:

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|px|alt=Statin Pathway edit]]

Statin Pathway edit

^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Inhibitors

Drugs

Drugs that inhibit HMG-CoA reductase, known collectively as HMG-CoA reductase inhibitors (or "statins"), are used to lower serum cholesterol as a means of reducing the risk for cardiovascular disease.^[8]

These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), pitavastatin (Livalo), and simvastatin (Zocor).^[9] Red yeast rice extract, one of the fungal sources from which the statins were discovered, contains several naturally occurring cholesterol-lowering molecules known as monacolins. The most active of these is monacolin K, or lovastatin (previously sold under the trade name Mevacor, and now available as generic lovastatin).^[10]

Vytorin is drug that combines the use simvastatin and ezetimibe, which slows the formation of cholesterol by every cell in the body, along with ezetimibe reducing absorption of cholesterol, typically by about 53%, from the intestines.^[11]

Hormones

HMG-CoA reductase is active when blood glucose is high. The basic functions of insulin and glucagon are to maintain glucose homeostasis. Thus, in controlling blood sugar levels, they indirectly affect the activity of HMG-CoA reductase, but a decrease in activity of the enzyme is caused by AMP-activated protein kinase^[12], which responds to an increase in AMP concentration, and also to leptin

Clinical significance

Since the reaction catalysed by HMG-CoA reductase is the rate-limiting step in cholesterol synthesis, this enzyme represents the sole major drug target for contemporary cholesterol-lowering drugs in humans. The medical significance of HMG-CoA reductase has continued to expand beyond its direct role in cholesterol synthesis following the discovery that statins can offer cardiovascular health benefits independent of cholesterol reduction.^[13] Statins have been shown to have anti-inflammatory properties,^[14] most likely as a result of their ability to limit production of key downstream isoprenoids that are required for portions of the inflammatory response. It can be noted that blocking of isoprenoid synthesis by statins has shown promise in treating a mouse model of multiple sclerosis, an inflammatory autoimmune disease.^[15]

HMG-CoA reductase is an important developmental enzyme. Inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to germ cell migration defects ^[16] as well as intracerebral hemorrhage.^[17]

Regulation

HMG-CoA reductase-Substrate complex (Blue:Coenzyme A, red:HMG, green:NADP)

Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.

Transcription of the reductase gene

Transcription of the reductase gene is enhanced by the sterol regulatory element binding protein (SREBP). This protein binds to the sterol regulatory element (SRE), located on the 5' end of the reductase gene after controlled proteolytic processing. When SREBP is inactive, it is bound to the ER or nuclear membrane with another protein called SREBP cleavage-activating protein (SCAP). SCAP senses low cholesterol concentration and transports SREBP to the Golgi membrane where a consecutive proteolysis by S1P and S2P cleaves SREBP into a active nuclear form, nSREBP. nSREBPs migrate to the nucleus and activate transcription of SRE-containing genes. The nSREBP transcription factor is short-lived. If cholesterol levels rise, SCAP retains SREBP in the ER membrane.

Translation of mRNA

Translation of mRNA is inhibited by a mevalonate derivative, which has been reported to be the isoprenoid farnesol,^[18]^[19] although this role has been disputed.^[20]

Degradation of reductase

Rising levels of sterols increase the susceptibility of the reductase enzyme to ER-associated degradation (ERAD) and proteolysis. Helices 2-6 (total of 8) of the HMG-CoA reductase transmembrane domain sense the higher levels of cholesterol, which leads to the exposure of Lysine 248. This lysine residue can become ubiquinated by the E3 ligase AMFR, serving as a signal for proteolytic degradation.

Phosphorylation of reductase

Short-term regulation of HMG-CoA reductase is achieved by inhibition by phosphorylation (of Serine 872, in humans^[21]). Decades ago it was believed that a cascade of enzymes controls the activity of HMG-CoA reductase: an HMG-CoA reductase kinase was thought to inactivate the enzyme, and the kinase in turn was held to be activated via phosphorylation by HMG-CoA reductase kinase kinase. An excellent review on regulation of the mevalonate pathway by Nobel Laureates Joseph Goldstein and Michael Brown adds specifics: HMG-CoA reductase is phosphorylated and inactivated by an AMP-activated protein kinase, which also phosphorylates and inactivates acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid biosynthesis.^[22] Thus, both pathways utilizing acetyl-CoA for lipid synthesis are inactivated when energy charge is low in the cell, and concentrations of AMP rise. There has been a great deal of research on the identity of upstream kinases that phosphorylate and activate the AMP-activated protein kinase.^[23]

Fairly recently, LKB1 has been identified as a likely AMP kinase kinase,^[24] which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules.^[23]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000113161 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021670 - Ensembl, May 2017
^ "Human PubMed Reference:".
^ "Mouse PubMed Reference:".
^ "Entrez Gene: HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase".
^ Roitelman J, Olender EH, Bar-Nun S, Dunn WA, Simoni RD (Jun 1992). "Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum". The Journal of Cell Biology. 117 (5): 959–73. doi:10.1083/jcb.117.5.959. PMC 2289486 . PMID 1374417.
^ Lindgren V, Luskey KL, Russell DW, Francke U (Dec 1985). "Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes". Proceedings of the National Academy of Sciences of the United States of America. 82 (24): 8567–71. Bibcode:1985PNAS...82.8567L. doi:10.1073/pnas.82.24.8567. PMC 390958 . PMID 3866240.
^ Farmer JA (1998). "Aggressive lipid therapy in the statin era". Progress in Cardiovascular Diseases. 41 (2): 71–94. doi:10.1016/S0033-0620(98)80006-6. PMID 9790411.
^ "Is there a "best" statin drug?". The Johns Hopkins Medical Letter Health After 50. 15 (11): 4–5. Jan 2004. PMID 14983817.
^ Lin YL, Wang TH, Lee MH, Su NW (Jan 2008). "Biologically active components and nutraceuticals in the Monascus-fermented rice: a review". Applied Microbiology and Biotechnology. 77 (5): 965–73. doi:10.1007/s00253-007-1256-6. PMID 18038131.
^ Flores NA (Sep 2004). "Ezetimibe + simvastatin (Merck/Schering-Plough)". Current Opinion in Investigational Drugs. 5 (9): 984–92. PMID 15503655.
^ Hardie DG (February 1992). "Regulation of fatty acid and cholesterol metabolism by the AMP-activated protein kinase". Biochimica et Biophysica Acta. 1123 (3): 231–8. doi:10.1016/0005-2760(92)90001-c. PMID 1536860.
^ Arnaud C, Veillard NR, Mach F (Apr 2005). "Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis". Current Drug Targets. Cardiovascular & Haematological Disorders. 5 (2): 127–34. doi:10.2174/1568006043586198. PMID 15853754.
^ Sorrentino S, Landmesser U (Dec 2005). "Nonlipid-lowering effects of statins". Current Treatment Options in Cardiovascular Medicine. 7 (6): 459–466. doi:10.1007/s11936-005-0031-1. PMID 16283973.
^ Stüve O, Youssef S, Steinman L, Zamvil SS (Jun 2003). "Statins as potential therapeutic agents in neuroinflammatory disorders". Current Opinion in Neurology. 16 (3): 393–401. doi:10.1097/00019052-200306000-00021. PMID 12858078.
^ Thorpe JL, Doitsidou M, Ho SY, Raz E, Farber SA (Feb 2004). "Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation". Developmental Cell. 6 (2): 295–302. doi:10.1016/S1534-5807(04)00032-2. PMID 14960282.
^ Eisa-Beygi S, Hatch G, Noble S, Ekker M, Moon TW (Jan 2013). "The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway". Developmental Biology. 373 (2): 258–266. doi:10.1016/j.ydbio.2012.11.024. PMID 23206891.
^ Meigs TE, Roseman DS, Simoni RD (Apr 1996). "Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol in vivo". The Journal of Biological Chemistry. 271 (14): 7916–22. doi:10.1074/jbc.271.14.7916. PMID 8626470.
^ Meigs TE, Simoni RD (Sep 1997). "Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase". Archives of Biochemistry and Biophysics. 345 (1): 1–9. doi:10.1006/abbi.1997.0200. PMID 9281305.
^ Keller RK, Zhao Z, Chambers C, Ness GC (Apr 1996). "Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver". Archives of Biochemistry and Biophysics. 328 (2): 324–30. doi:10.1006/abbi.1996.0180. PMID 8645011.
^ Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J (Mar 2000). "Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis". The EMBO Journal. 19 (5): 819–30. doi:10.1093/emboj/19.5.819. PMC 305622 . PMID 10698924.
^ Goldstein JL, Brown MS (Feb 1990). "Regulation of the mevalonate pathway". Nature. 343 (6257): 425–30. Bibcode:1990Natur.343..425G. doi:10.1038/343425a0. PMID 1967820.
^ ^a ^b Hardie DG, Scott JW, Pan DA, Hudson ER (Jul 2003). "Management of cellular energy by the AMP-activated protein kinase system". FEBS Letters. 546 (1): 113–20. doi:10.1016/S0014-5793(03)00560-X. PMID 12829246.
^ Witters LA, Kemp BE, Means AR (Jan 2006). "Chutes and Ladders: the search for protein kinases that act on AMPK". Trends in Biochemical Sciences. 31 (1): 13–6. doi:10.1016/j.tibs.2005.11.009. PMID 16356723.

External links

Cholesterol Synthesis - has some good regulatory details
Proteopedia HMG-CoA_Reductase - the HMG-CoA Reductase Structure in Interactive 3D

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. スタチン：作用、副作用、および投与 statins actions side effects and administration
2. スタチン誘発性ミオパチー statin myopathy
3. 高IgD症候群：病態生理 hyperimmunoglobulin d syndrome pathophysiology
4. 胆石の溶解療法 dissolution therapy for the treatment of gallstones
5. 脳腱黄色腫症 cerebrotendinous xanthomatosis

English Journal

Reversal of high fat diet-induced obesity through modulating lipid metabolic enzymes and inflammatory markers expressions in rats.

A K, Uddandrao VVS, Parim B, Ganapathy S, P R N, Kancharla SC, P R, K S, Sasikumar V.
Archives of physiology and biochemistry. 2019 Jul;125(3)228-234.
In this study, we evaluated the ameliorative potential of Cucurbita maxima seeds oil (CSO (100 mg/kg body weight)) supplementation to high fat diet (HFD)-induced obese rats for 30 days on the changes in body weight, markers of lipid metabolism such as LDL, HDL, triglycerides, total cholesterol, a
PMID 29553847

Elimination of adrenocortical apolipoprotein E production does not impact glucocorticoid output in wild-type mice.

van der Sluis RJ, Depuydt MAC, Verwilligen RAF, Hoekstra M, Van Eck M.
Molecular and cellular endocrinology. 2019 Jun;490()21-27.
Apolipoprotein E (APOE) deficient mice exhibit unexplained hypercorticosteronemia. Given that APOE is also produced locally within the adrenals, we evaluated the effect of adrenal-specific APOE deficiency on the glucocorticoid function. Hereto, one adrenal containing or lacking APOE was transplanted
PMID 30953750

Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR).

Zhang Y, Zhang X, Zeng C, Li B, Zhang C, Li W, Hou X, Dong Y.
Bioorganic & medicinal chemistry. 2019 Jun;27(11)2187-2191.
Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N-acetylgalactosamine) onto atorvastatin (AT
PMID 31005367

Japanese Journal

ATF6α Stimulates Cholesterogenic Gene Expression and de Novo Cholesterol Synthesis

MARUYAMA Ryuto,KAMOSHIDA Yuki,SHIMIZU Makoto,INOUE Jun,SATO Ryuichiro
Bioscience, Biotechnology, and Biochemistry, 2013
… Here we found that forced expression of a constitutively active form of ATF6α, ATF6(N), stimulated the expression of cholesterogenic genes, including 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, HMG-CoA synthase, and squalene synthase, and de novo cholesterol synthesis in hepatoma Huh-7 cells. …
NAID 130003361197

Dietary Effects of Pure and Diacylglycerol-rich Rice Bran Oil on Growth Pattern and Lipid Profile of Rats

Dhara Rupali,Dhar Pubali,Ghosh Mahua
Journal of Oleo Science 61(7), 369-375, 2012-07-00
NAID 40019309903

Effects of Pitavastatin on Pressure Overload-Induced Heart Failure in Mice

KAMEDA Yoshihito,HASEGAWA Hiroshi,KUBOTA Akihiko,TADOKORO Hiroyuki,KOBAYASHI Yoshio,KOMURO Issei,TAKANO Hiroyuki
Circulation journal : official journal of the Japanese Circulation Society 76(5), 1159-1168, 2012-04-25
… Background: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are widely used to lower plasma cholesterol levels, have been reported to have various pleiotropic effects such as protective effect of endothelial cells, angiogenic effect, antioxidant effect and anti-inflammatory effect. …
NAID 10030132534

★リンクテーブル★

リンク元	「HMG-CoA還元酵素阻害薬」「コレステロール」「解糖系」「リポ蛋白(a)」「代謝系」
拡張検索	「HMG-CoA reductase inhibitor」「HMG-CoA reductase inhibitors」
関連記事	「C」「reductase」「HMG」「CoA」「H」

「HMG-CoA還元酵素阻害薬」

hydroxymethylglutaryl-CoA reductase
Identifiers
EC number	1.1.1.88
CAS number	37250-24-1
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search
PMC	articles
PubMed	articles
NCBI	proteins

HMG-CoA reductase
EC number	{{{EC_number}}}
Gene Ontology	AmiGO / QuickGO

HMGCR
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1DQ8, 1DQ9, 1DQA, 1HW8, 1HW9, 1HWI, 1HWJ, 1HWK, 1HWL, 2Q1L, 2Q6B, 2Q6C, 2R4F, 3BGL, 3CCT, 3CCW, 3CCZ, 3CD0, 3CD5, 3CD7, 3CDA, 3CDB
Identifiers
Aliases	HMGCR, HMG-CoA reductase, Entrez 3156, LDLCQ3, 3-hydroxy-3-methylglutaryl-CoA reductase, Hydroxymethylglutaryl-CoA reductase
External IDs	OMIM: 142910 MGI: 96159 HomoloGene: 30994 GeneCards: HMGCR
Gene location (Human)
Chr.	Chromosome 5 (human)
End	75,362,104 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	96,670,936 bp
RNA expression pattern
	; ;
	More reference expression data
Gene ontology
Molecular function	• oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor; • protein homodimerization activity; • hydroxymethylglutaryl-CoA reductase (NADPH) activity; • protein binding; • NADP binding; • NADPH binding; • coenzyme binding; • oxidoreductase activity; • hydroxymethylglutaryl-CoA reductase activity;
Cellular component	• integral component of membrane; • endoplasmic reticulum membrane; • membrane; • intracellular membrane-bounded organelle; • peroxisomal membrane; • endoplasmic reticulum;
Biological process	• visual learning; • steroid metabolic process; • sterol biosynthetic process; • negative regulation of striated muscle cell apoptotic process; • coenzyme A metabolic process; • response to nutrient; • positive regulation of skeletal muscle tissue development; • lipid metabolic process; • positive regulation of cardiac muscle cell apoptotic process; • negative regulation of insulin secretion involved in cellular response to glucose stimulus; • aging; • negative regulation of apoptotic process; • cholesterol metabolic process; • protein tetramerization; • isoprenoid biosynthetic process; • negative regulation of MAP kinase activity; • positive regulation of cell proliferation; • positive regulation of ERK1 and ERK2 cascade; • negative regulation of wound healing; • cholesterol biosynthetic process; • ubiquinone metabolic process; • myoblast differentiation; • response to ethanol; • oxidation-reduction process; • positive regulation of stress-activated MAPK cascade; • positive regulation of smooth muscle cell proliferation; • steroid biosynthetic process; • regulation of lipid metabolic process; • regulation of cholesterol biosynthetic process; • negative regulation of blood vessel diameter;
	Sources:Amigo / QuickGO
Orthologs
	3156
	15357
	ENSG00000113161
	ENSMUSG00000021670
	P04035
	Q01237
	NM_000859; NM_001130996
	NM_008255; NM_001360165; NM_001360166
	NP_000850; NP_001124468; NP_000850.1
	NP_032281; NP_001347094; NP_001347095
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: HMG-CoA reductase inhibitor
同: ヒドロキシメチルグルタリルコエンザイムA還元酵素阻害薬 hydroxymethylglutaryl-CoA reductase inhibitor。スタチン statin
関: 高脂血症治療薬、高脂血症、コレステロールの生合成。HMG-CoA還元酵素 HMG-CoA reductase

特徴

強力なコレステロール低下作用

アトルバスタチンの場合

血清TC低下率30%

血清LDL-C低下率41%

血清TG低下作用

TG250-350mg/dl　380

TG350-450mg/dl　470

安全性が高い(プラバスタチンのみ)

プラバスタチンは水溶性。(⇔脂溶性だとどこでも入っていく→全身性に作用する)

プラバスタチンの輸送担体は肝臓にしかない→臓器選択性↑→安全性↑

CYP3A4との相互作用がない

種類

CYP 代謝による分類	薬物	商品名	性質1)		CYP代謝 2)	代謝物の活性 3)	排泄形態 3)	bioavailability (%) 3)	尿中排泄 (%) 2)	半減期 (hr) 2)
CYP 代謝による分類	薬物	商品名	定性	定量(LogP)	CYP代謝 2)	代謝物の活性 3)	排泄形態 3)	bioavailability (%) 3)	尿中排泄 (%) 2)	半減期 (hr) 2)
非代謝型	プラバスタチン	メバロチン	水溶性	-0.47	ほとんどなし	ー	未変化体	18	20	1ー2
	ロスバスタチン	クレストール	水溶性			ー 5)	未変化体 5)	29	10 5)	15～19 5)
	ピタバスタチン	リバロ	脂溶性	1.49		ー	未変化体	60	＜2	11
代謝型	フルバスタチン	ローコール	脂溶性	1.73	CYP2C9	なし	代謝物	10-35	＜6	1.2
	シンバスタチン	リポバス	脂溶性	4.4	CYP3A4	あり	代謝物	＜5	13	1ー2
	アトルバスタチン	リピトール	脂溶性	1.53	CYP3A4	あり	(データ無し)	12	2	14
1)Prog Med, 18:957-962,1998. 2)Heart, 85:259-264,2001. 3)PHarmacol Ther, 80:1-34 改変 4)興和(株)社内資料 5)添付文書

作用機序

HMG-CoA reductaseを競合阻害→肝内コレステロール産生↓→肝LDL受容体発現↑→血中LDL↓

HMG-CoA reductaseはHMG-CoAからmevalonate産生を触媒

副作用

1. 横紋筋融解症

原因：メバロン酸合成↓→CoQ↓→ミトコンドリア機能異常。Cl^-の細胞膜透過性の変化

2. CYPを介する薬物相互作用

CYP	代謝されるスタチン	代謝される薬物	強く阻害する薬物
CYP2C9	フルバスタチン	ワーファリンジクロフェナクフェニトイン	サルファ剤 ST合剤
CYP3A4	シンバスタチンセリバスタチンアトルバスタチン	ニフェジピンシクロスポリンジルチアゼムなど多数	エリスロマイシンシメチジンイトラコナゾールベラパミル

薬物相互作用によりCYP3A4の働きが阻害されると、横紋筋融解症の引き金となりうる

3. 肝障害

脂溶性HMG-CoA還元酵素阻害薬は重篤な肝障害を起こす

4. CK上昇

This was suggested by a study showing greater increases in post-marathon CK levels in individuals receiving statins; older runners receiving statins exhibited more susceptibility to CK elevations than younger runners. These elevations in CK were, however, mild and subclinical, which suggests that trained individuals need not discontinue statin therapy prior to a race.(uptodate)

軽度であれば(マラソンの)習熟者はレース前にスタチンを中止をする必要がないことを示唆する。

禁忌

妊婦

「コレステロール」

　　[★]

英: cholesterol
同: コレステリン cholesterin
関: lipoprotein

コレステロールは多くの場合、長鎖脂肪酸のコレステロールエステルとして食品に多く含まれる (SP.739)

分子式

C27H46O = 386.66

吸収

小腸から放出された脂質とコレステロールはアポ蛋白とカイロミクロンを形成する。
カイロミクロンは血液循環に入り、循環中にカイロミクロンレムナント chylomicron remnantとなる。

カイロミクロンに含まれる脂質は、血管内皮に存在するリポ蛋白リパーゼ(LPL)により分解されて脂肪酸を遊離し、コレステロールの比が高いカイロミクロンレムナントとなる。

肝臓はカイロミクロンレムナントを取り込む

生合成

コレステロールは酢酸を原料として合成される。

acetyl-CoA→hydroxymethyl-glutaryl coenzyme A(HMG-CoA)－(HMG-CoA reductase)→mebaronate→･･･→コレステロール

→コレステロールの生合成

体内循環

肝臓は血液循環にVLDLを放出する

血液循環中のVLDLの脂質は、、血管内皮に存在するリポ蛋白リパーゼ(LPL)により分解されて脂肪酸を遊離し、コレステロールの比が高いIDL、LDLとなる。

組織からはコレステロール比型が高いHDLが放出され、そのまま肝臓に取り込まれるか、IDLにコレステロールを渡すことでコレステロールの逆輸送を行っている(内因性の抗動脈硬化作用)。

肝臓は血液循環からHDL, IDL, VDLを受容体を介して取り込む

排泄

肝臓でコレステロールは胆汁酸に変換され、胆汁として排出される

see HBC.236

Lipoprotein	Source	Diameter (nm)	Density (g/mL)	Composition		Main Lipid Components	Apolipoproteins
				Protein	Lipid
				(%)	(%)
Chylomicrons	Intestine	90～100	< 0.95	1～2	98.99	Triacylglycerol	A-I, A-II, A-IV,1 B-48, C-I, C-II, C-III, E
Chylomicron remnants	Chylomicrons	45～150	< 1.006	6～8	92.94	Triacylglycerol, phospholipids, cholesterol	B-48, E
VLDL	Liver (intestine)	30～90	0.95～1.006	7～10	90～93	Triacylglycerol	B-100, C-I, C-II, C-III
IDL	VLDL	25～35	1.006～1.019	11	89	Triacylglycerol, cholesterol	B-100, E
LDL	VLDL	20～25	1.019～1.063	21	79	Cholesterol	B-100
HDL1	Liver, intestine, VLDL, chylomicrons	20～25	1.019.1.063	32	68	Phospholipids, cholesterol	A-I, A-II, A-IV, C-I, C-II, C-III, D,2 E
HDL2		10～20	1.063～1.125	33	67
HDL3		5～10	1.125～1.210	57	43
Preβ-HDL3		< 5	> 1.210				A-I
Albumin/free fatty	Adipose acids tissue		> 1.281	99	1	Free fatty acids

基準値

総コレステロール　：＜220 mg/dl
HDLコレステロール：≧40 mg/dl
LDLコレステロール：＜140 mg/dl

脂質異常症→　血清：Total-CHO≧220 mg/dl。LDL-C≧140 mg/dl。TG≧150 mg/dl。HDL-C＜40 mg/dl

参考

1.

http://rockymuku.sakura.ne.jp/naibunnpitunaika/koresutero-runotanninokannzann.pdf

「解糖系」

　　[★]

英: glycolytic pathway
同: エムデン-マイヤーホフ経路 Embden-Meyerhof pathway
関: 解糖、TCA回路

CH(OH)-CH(OH)-C(OH)H-CH(OH)-C(CH2OH)H-O- グルコース (OHが↓↓↑↓↑)
CH(OH)-CH(OH)-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- グルコース-6-リン酸 (OHが↓↓↑↓↑)
C(CH2OH)OH-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- フルクトース-6-リン酸
C(CH2O-PO3)OH-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- フルクトース-1,6-リン酸

glucose
↓-hexokinase/glucokinase(liver)
glucose 6-phosphate
↓-phosphohexose isomerase
fructose 6-phosphate
↓-phosphofructokinase
fructose 1,6-bisphosphate
↓-aldolase
glyceraldehyde 3-phosphate
↓-glyceraldehyde-3-phosphate dehydrogenase
1,3-bisphosphoglycerate
↓-phosphoglycerate kinase →ATP
3-phosphoglycerate
↓-phosphoglyceate mutase
2-phosphoglycerate
↓-enolase
phosphoenolpyruvate
↓-pyruvate kinase → ATP
pyruvate
　－(pyruvate dehydrogenase)→acetyl-CoA
　－(pyruvate carboxylase)→oxaloacetate－(NADH+H+)→malate

解糖系の酵素 (first aid step1 2006 p.87, FASTEP1_87_酵素一覧.xls)

1	galactokinase	キナーゼ
2	galactose-1-phosphate uridyltransferase	転移酵素
3	hexokinase/glucokinase	キナーゼ
4	glucose-6-phosphatase	ホスファターゼ
5	glucose-6-phosphate dehydrogenase	脱水素酵素
6	transketolase
7	phosphofructokinase	キナーゼ
8	fructose-1,6-bisphosphatase	ホスファターゼ
9	fructokinase	キナーゼ	フルクトキナーゼ
10	aldolase B		アルドラーゼ
11	pyruvate kinase	キナーゼ	ピルビン酸キナーゼ
12	pyruvate dehydrogenase	脱水素酵素	ピルビン酸デヒドロゲナーゼ
13	HMG-CoA reductase	還元酵素	HMG-CoA還元酵素
14	pyruvate carboxylase	カルボキシラーゼ	ピルビン酸カルボキシラーゼ
15	PEP carboxykinase	キナーゼ	PEPカルボキシキナーゼ
16	citrate synthase	合成酵素	クエン酸合成酵素
17	α-ketoglutarate dehydrogenase	脱水素酵素	α-ケトグルタミン酸脱水素酵素
18	ornithine transcarbamylase	転移酵素	オルニチンカルバモイルトランスフェラーゼ

「リポ蛋白(a)」

　　[★]

英: lipoprotein (a), lipoprotein(a) Lp(a)
同: リポ蛋白A、リポタンパク質(a)、リポプロテイン(a)
関: LDL、HDL

[show details]

リポ蛋白 : 約 88,800 件
リポ蛋白質 : 約 35,100 件
リポタンパク : 約 32,700 件
リポタンパク質 : 約 75,800 件
リポプロテイン : 約 13,200 件

リポ蛋白(a) : 約 52,200 件
リポ蛋白質(a) : 29 件
リポタンパク(a) : 56 件
リポタンパク質(a) : 40 件
リポプロテイン(a) : 約 23,900 件

リポタンパク質の一つ。密度で分画したときに出現する。
LDLにアポリポタンパク質Bを介してアポリポタンパク質(a)が結合している。
動脈硬化の危険因子とされる
血中濃度：は糖尿病↑、腎疾患↑、高中性脂肪血症↓、HMG-CoA reductase→、ニコチン酸系薬↓

「代謝系」

　　[★]

英: metabolic pathway
関: 代謝経路

解糖系
TCA回路
電子伝達系
尿酸回路
糖新生経路

1 galactokinase
2 galactose-1-phosphate uridyltransferase
3 hexokinase/glucokinase
4 glucose-6-phosphatase
5 glucose-6-phosphate dehydrogenase
6 transketolase
7 phosphofructokinase
8 fructose-1,6-bisphosphatase
9 fructokinase
10 aldolase B
11 pyruvate kinase
12 pyruvate dehydrogenase
13 HMG-CoA reductase
14 pyruvate carboxylase
15 PEP carboxykinase
16 citrate synthase
17 α-ketoglutarate dehydrogenase
18 ornithine transcarbamylase

「HMG-CoA reductase inhibitor」

　　[★] HMG-CoA還元酵素阻害薬

「HMG-CoA reductase inhibitors」