Posttranslational Regulation of HMG CoA Reductase, the Rate-Limiting Enzyme in Synthesis of Cholesterol

2021 ◽  
Vol 90 (1) ◽  
pp. 659-679
Author(s):  
Marc M. Schumacher ◽  
Russell A. DeBose-Boyd
Keyword(s):  
Endoplasmic Reticulum ◽  
Cholesterol Metabolism ◽  
Posttranslational Regulation ◽  
Hmg Coa Reductase ◽  
Feedback Mechanisms ◽  
Genetically Manipulated ◽  
Coa Reductase ◽  
Rate Limiting

The polytopic, endoplasmic reticulum (ER) membrane protein 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, the key intermediate in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). Transcriptional, translational, and posttranslational feedback mechanisms converge on this reductase to ensure cells maintain a sufficient supply of essential nonsterol isoprenoids but avoid overaccumulation of cholesterol and other sterols. The focus of this review is mechanisms for the posttranslational regulation of HMG CoA reductase, which include sterol-accelerated ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. We discuss how GGpp-induced ER-to-Golgi trafficking of the vitamin K2 synthetic enzyme UbiA prenyltransferase domain–containing protein-1 (UBIAD1) modulates HMG CoA reductase ERAD to balance the synthesis of sterol and nonsterol isoprenoids. We also summarize the characterization of genetically manipulated mice, which established that sterol-accelerated, UBIAD1-modulated ERAD plays a major role in regulation of HMG CoA reductase and cholesterol metabolism in vivo.

scholarly journals Inhibition of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase (Ex Vivo) by Morus indica (Mulberry)

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Vanitha Reddy Palvai ◽  
Asna Urooj
Keyword(s):  
Coenzyme A ◽  
Cholesterol Metabolism ◽  
Ex Vivo ◽  
Plasma Cholesterol ◽  
Effective Means ◽  
Inhibitory Effect ◽  
Hmg Coa Reductase ◽  
Standard Drug ◽  
Coa Reductase

Phytochemicals are the bioactive components that contribute to the prevention of cardiovascular and other degenerative diseases. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase would be an effective means of lowering plasma cholesterol in humans. The present study explores the HMG CoA reductase inhibitory effect of extracts from leaves of Morus indica varieties, M5, V1, and S36, compared with the statin, using an ex vivo method. The assay is based on the stoichiometric formation of coenzyme A during the reduction of microsomal HMG CoA to mevalonate. Dechlorophyllised extract of three varieties was studied at 300 µg. The coenzyme A released at the end of assay in control (100.31 nmoles) and statins (94.46 nm) was higher than the dechlorphyllised extracts of the samples. The coenzyme A released during the reduction of HMG CoA to mevalonate in dechlorophyllised extracts of the samples was as follows: S36 < M5 < V1. The results indicated that the samples were highly effective in inhibiting the enzyme compared to statins (standard drug). The results indicate the role of Morus varieties extracts in modulating the cholesterol metabolism by inhibiting the activity of HMG CoA reductase. These results provide scope for designing in vivo animal studies to confirm their effect.

scholarly journals Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Rania Elsabrouty ◽  
Youngah Jo ◽  
Seonghwan Hwang ◽  
Dong-Jae Jun ◽  
Russell A DeBose-Boyd
Keyword(s):  
Endoplasmic Reticulum ◽  
Vitamin K ◽  
Feedback Mechanism ◽  
Hmg Coa Reductase ◽  
Golgi Transport ◽  
Coa Reductase ◽  
Rate Limiting ◽  
Hydrolysis Of ◽  
Alcohol Derivative

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. The prenyltransferase has emerged as a key regulator of sterol-accelerated, endoplasmic reticulum (ER)-associated degradation (ERAD) of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Sterols induce binding of UBIAD1 to reductase, inhibiting its ERAD. Geranylgeraniol (GGOH), the alcohol derivative of GGpp, disrupts this binding and thereby stimulates ERAD of reductase and translocation of UBIAD1 to Golgi. We now show that overexpression of Type 1 polyisoprenoid diphosphate phosphatase (PDP1), which dephosphorylates GGpp and other isoprenyl pyrophosphates to corresponding isoprenols, abolishes protein geranylgeranylation as well as GGOH-induced ERAD of reductase and Golgi transport of UBIAD1. Conversely, these reactions are enhanced in the absence of PDP1. Our findings indicate PDP1-mediated hydrolysis of GGpp significantly contributes to a feedback mechanism that maintains optimal intracellular levels of the nonsterol isoprenoid.

scholarly journals Dislocation of HMG-CoA Reductase and Insig-1, Two Polytopic Endoplasmic Reticulum Proteins, En Route to Proteasomal Degradation

2009 ◽  
Vol 20 (14) ◽  
pp. 3330-3341 ◽  
Author(s):  
Gil S. Leichner ◽  
Rachel Avner ◽  
Dror Harats ◽  
Joseph Roitelman
Keyword(s):  
Endoplasmic Reticulum ◽  
Proteasomal Degradation ◽  
Metabolic Energy ◽  
Wild Type ◽  
Hmg Coa Reductase ◽  
Aaa Atpase ◽  
Rate Limiting Step ◽  
Coa Reductase ◽  
Rate Limiting ◽  
Membrane Region

The endoplasmic reticulum (ER) glycoprotein HMG-CoA reductase (HMGR) catalyzes the rate-limiting step in sterols biosynthesis. Mammalian HMGR is ubiquitinated and degraded by the proteasome when sterols accumulate in cells, representing the best example for metabolically controlled ER-associated degradation (ERAD). This regulated degradation involves the short-lived ER protein Insig-1. Here, we investigated the dislocation of these ERAD substrates to the cytosol en route to proteasomal degradation. We show that the tagged HMGR membrane region, HMG350-HA, the endogenous HMGR, and Insig-1-Myc, all polytopic membrane proteins, dislocate to the cytosol as intact full-length polypeptides. Dislocation of HMG350-HA and Insig-1-Myc requires metabolic energy and involves the AAA-ATPase p97/VCP. Sterols stimulate HMG350-HA and HMGR release to the cytosol concurrent with removal of their N-glycan by cytosolic peptide:N-glycanase. Sterols neither accelerate dislocation nor stimulate deglycosylation of ubiquitination-defective HMG350-HA(K89 + 248R) mutant. Dislocation of HMG350-HA depends on Insig-1-Myc, whose dislocation and degradation are sterol independent. Coimmunoprecipitation experiments demonstrate sterol-stimulated association between HMG350-HA and Insig-1-Myc. Sterols do not enhance binding to Insig-1-Myc of HMG350-HA mutated in its sterol-sensing domain or of HMG350-HA(K89 + 248R). Wild-type HMG350-HA and Insig-1-Myc coimmunoprecipitate from the soluble fraction only when both proteins were coexpressed in the same cell, indicating their encounter before or during dislocation, raising the possibility that they are dislocated as a tightly bound complex.

In Vivo LDL Receptor and HMG-CoA Reductase Regulation in Human Lymphocytes and Its Alterations During Aging

1995 ◽  
Vol 15 (7) ◽  
pp. 872-878 ◽  
Author(s):  
Thomas M. Stulnig ◽  
Helmut Klocker ◽  
H. James Harwood ◽  
Günther Jürgens ◽  
Dieter Schönitzer ◽  
...  
Keyword(s):  
Human Lymphocytes ◽  
Ldl Receptor ◽  
Hmg Coa Reductase ◽  
Coa Reductase

scholarly journals The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sam A Menzies ◽  
Norbert Volkmar ◽  
Dick JH van den Boomen ◽  
Richard T Timms ◽  
Anna S Dickson ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Critical Role ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Editorial Note ◽  
Hmg Coa Reductase ◽  
Genome Wide ◽  
Cholesterol Biosynthetic Pathway ◽  
Coa Reductase ◽  
Rate Limiting

Mammalian HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthetic pathway and the therapeutic target of statins, is post-transcriptionally regulated by sterol-accelerated degradation. Under cholesterol-replete conditions, HMGCR is ubiquitinated and degraded, but the identity of the E3 ubiquitin ligase(s) responsible for mammalian HMGCR turnover remains controversial. Using systematic, unbiased CRISPR/Cas9 genome-wide screens with a sterol-sensitive endogenous HMGCR reporter, we comprehensively map the E3 ligase landscape required for sterol-accelerated HMGCR degradation. We find that RNF145 and gp78 independently co-ordinate HMGCR ubiquitination and degradation. RNF145, a sterol-responsive ER-resident E3 ligase, is unstable but accumulates following sterol depletion. Sterol addition triggers RNF145 recruitment to HMGCR via Insigs, promoting HMGCR ubiquitination and proteasome-mediated degradation. In the absence of both RNF145 and gp78, Hrd1, a third UBE2G2-dependent E3 ligase, partially regulates HMGCR activity. Our findings reveal a critical role for the sterol-responsive RNF145 in HMGCR regulation and elucidate the complexity of sterol-accelerated HMGCR degradation.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

Bile duct cells: a novel in vitro model for the study of lipid metabolism and bile acid production

1999 ◽  
Vol 276 (2) ◽  
pp. G407-G414 ◽  
Author(s):  
Monika Zoltowska ◽  
Edgard E. Delvin ◽  
Khazal Paradis ◽  
Ernest Seidman ◽  
Emile Levy
Keyword(s):  
Bile Acid ◽  
Bile Duct ◽  
Bile Acids ◽  
Cytokeratin 19 ◽  
Sterol Metabolism ◽  
Hmg Coa Reductase ◽  
Biliary Epithelium ◽  
Duct Cells ◽  
Coa Reductase

Immortalized bile duct cells (BDC), derived from transgenic mice harboring the SV40 thermosensitive immortalizing mutant gene ts458, were utilized to investigate the role of the biliary epithelium in lipid and sterol metabolism. This cell model closely resembles the in vivo situation because it expresses the specific phenotypic marker cytokeratin 19 (CK-19), exhibits the formation of bile duct-like structures, and displays well-formed microvilli projected from the apical side to central lumen. The BDC were found to incorporate [14C]oleic acid (in nmol/mg protein) into triglycerides (121 ± 6), phospholipids (PL; 59 ± 3), and cholesteryl ester (16 ± 1). The medium lipid content represented 5.90 ± 0.16% ( P < 0.005) of the total intracellular production, indicating a limited lipid export capacity. Analysis of PL composition demonstrated the synthesis of all classes of polar lipids, with phosphatidylcholine and phosphatidylethanolamine accounting for 60 ± 1 and 24 ± 1%, respectively, of the total. Differences in PL distribution were apparent between cells and media. Substantial cholesterol synthesis was observed in BDC, as determined by the incorporation of [14C]acetate suggesting the presence of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. With the use of [14C]acetate and [14C]cholesterol as precursors, both tauro- and glycoconjugates of bile acids were synthesized, indicating the presence of cholesterol 7α- and 26R-hydroxylases, the key enzymes involved in bile acid formation. The transport of bile acids was not limited, as shown by their marked accumulation in the medium (>6-fold of cell content). HMG-CoA reductase (53.0 ± 6.7), cholesterol 7α-hydroxylase (15.5 ± 0.5), and acyl-CoA:cholesterol acyltransferase (ACAT; 201.7 ± 10.2) activities (in pmol ⋅ min−1 ⋅ mg protein−1) were present in the microsomal fractions. Our data show that biliary epithelial cells actively synthesize lipids and may directly contribute bile acids to the biliary fluid in vivo. This BDC line thus represents an efficient experimental tool to evaluate biliary epithelium sterol metabolism and to study biliary physiology.

scholarly journals An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro

Circulation ◽  
2001 ◽  
Vol 103 (2) ◽  
pp. 276-283 ◽  
Author(s):  
Masanori Aikawa ◽  
Elena Rabkin ◽  
Seigo Sugiyama ◽  
Sami J. Voglic ◽  
Yoshihiro Fukumoto ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Tissue Factor ◽  
Reductase Inhibitor ◽  
Hmg Coa Reductase ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase
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