Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol

Jiang, Shi-You; Li, Hui; Tang, Jinshan; Wang, Jie; Luo, Jie; Liu, Bing; Wang, Jin-Kai; Shi, Xiongjie; Cui, Hai-Wei; Tang, Jie; Yang, Fan; Qi, Wei; Qiu, Wen‐Wei; Song, Bao-Liang

doi:10.1038/s41467-018-07590-3

Cited by 131 publications

(99 citation statements)

References 69 publications

(87 reference statements)

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“…Importantly, the sterol regulatory network that governs HMGCR levels has been confirmed to be functional in vivo in mouse models. Knockout of gp78 stabilizes HMGCR and upregulates its activity in mouse liver (58), whilst intake of dimethylated sterol analogues leads to depletion of hepatic HMGCR and reduced serum cholesterol (59). Furthermore, levels of a transgenic protein comprising the sterol-sensing domain of HMGCR are increased or decreased by statin or cholesterol feeding, respectively (60), in agreement with previous cell culture experiments (52).…”

Section: The Classic Control Enzyme -Hmgcrsupporting

confidence: 84%

“…This collective understanding of sterol-induced HMGCR degradation will undoubtedly be of importance in the future development of cholesterol-lowering therapeutics. Such treatments may be useful in augmenting or substituting statins, which can lose efficacy over time or lead to severe withdrawal effects (61) due to compensatory upregulation of HMGCR gene expression and a decline in degradation-promoting sterol intermediates (59).…”

Section: The Classic Control Enzyme -Hmgcrmentioning

confidence: 99%

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Post-translational control of the long and winding road to cholesterol

Sharpe

Coates

Brown

2020

Journal of Biological Chemistry

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The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

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Section: The Classic Control Enzyme -Hmgcrsupporting

confidence: 84%

Section: The Classic Control Enzyme -Hmgcrmentioning

confidence: 99%

Post-translational control of the long and winding road to cholesterol

Sharpe

Coates

Brown

2020

Journal of Biological Chemistry

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“…We found that exogenously added lanosterol, 24,25-dihydrolanosterol (24,, or other 4,4-dimethylated sterols could stimulate HMGCR ubiquitination in vitro and HMGCR degradation in cultured cells (18). Recently, we developed a lanosterol derivative (named HMG499 or compound 81) that effectively degrades HMGCR in cultured cells and lowers diet-induced hypercholesterolemia in mice (27). Consistently, Nguyen et al (28) observed HMGCR degradation under hypoxia, a condition that causes lanosterol and 24,25-DHL accumulation because oxygens are indispensable for converting lanosterol to cholesterol.…”

mentioning

confidence: 99%

Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing

Chen

Yan

Sun

et al. 2019

Journal of Lipid Research

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Supplementary key words mevalonate • lanosterol • sterol intermediates • 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation • sterol regulatory element-binding protein-2 cleavage • clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) • sterol regulatory element-binding protein-2 Cholesterol is an essential lipid for mammals. It regulates membrane fluidity and functions, serves as the precursor for steroid hormones and bile acids, and covalently modifies the Hedgehog and Smoothened proteins (1-3). A high level of blood cholesterol is a major risk factor for cardiovascular disease, and cholesterol lowering is an effective way to treat the cardiovascular disease (4-7). Cholesterol is synthesized from acetyl-CoA through over 30 steps of reactions (Fig. 1). The cholesterol biosynthetic pathway is also known as the mevalonate pathway. Mevalonate is a key intermediate synthesized from HMG-CoA by HMG-CoA reductase (HMGCR), an ER-localized ratelimiting enzyme of the mevalonate pathway (8). Cholesterol biosynthesis is governed by two feedback regulatory mechanisms: the sterol-induced degradation of HMGCR (9) and inactivation of SREBP-2, the latter of which controls transcription of the genes involved in cholesterol biosynthesis and uptake (10). When the cellular sterol level is Abstract Sterol-regulated HMG-CoA reductase (HMGCR) degradation and SREBP-2 cleavage are two major feedback regulatory mechanisms governing cholesterol biosynthesis. Reportedly, lanosterol selectively stimulates HMGCR degradation, and cholesterol is a specific regulator of SREBP-2 cleavage. However, it is unclear whether other endogenously generated sterols regulate these events. Here, we investigated the sterol intermediates from the mevalonate pathway of cholesterol biosynthesis using a CRISPR/Cas9mediated genetic engineering approach. With a constructed HeLa cell line expressing the mevalonate transporter, we individually deleted genes encoding major enzymes in the mevalonate pathway, used lipidomics to measure sterol intermediates, and examined HMGCR and SREBP-2 statuses. We found that the C4-dimethylated sterol intermediates, including lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, and dihydro-testis meiosis activating sterol, were significantly upregulated upon mevalonate loading. These intermediates augmented both degradation of HMGCR and inhibition of SREBP-2 cleavage. The accumulated lanosterol induced rapid degradation of HMGCR, but did not inhibit SREBP-2 cleavage. The newly synthesized cholesterol from the mevalonate pathway is dispensable for inhibiting SREBP-2 cleavage. Together, these results suggest that lanosterol is a bona fide endogenous regulator that specifically promotes HMGCR degradation, and that other C4-dimethylated sterol intermediates may regulate both HMGCR degradation and SREBP-2 cleavage.

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“…Insulin deficiency is associated with decreased HMG CoA/mevalonate ratio indicating increased enzyme activity. Numerous studies have highlighted that the activity of HMG-CoA reductase is increased in diabetic rats [22].…”

Section: Discussionmentioning

confidence: 99%

Isopulegol Ameliorates Dyslipidemia by Modulating Adipokine Secretion in High Fat Diet / Streptozotocin Induced Diabetic Rats

Kalaivani¹,

Sankaranarayanan²

2019

J. Drug Delivery Ther.

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The present study investigates the effect of isopulegol on adipokine secretion and dyslipidemia in high fat diet and streptozotocin (HFD/STZ) induced diabetic rats. Animals were made diabetic by feeding HFD for 4 wks followed by single intraperitoneal injection of STZ (35mg/kg b.w; 0.1M citrate buffer; pH 4.0). Diabetic rats showed increased levels of total cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein-C (LDL-C), very low density lipoprotein -C (VLDL-C) and decreased high density lipoprotein-C levels (HDL-C). Similarly, the activity of HMG-CoA reductase, was increased while lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) activities were significantly decreased. Furthermore, the expression of sterol regulatory element binding protein-1C (SREBP-1C), adiponectin, peroxisome proliferator activated receptor gamma (PPARγ) were significantly down regulated, whereas leptin expression was upregulated in diabetic rats. Administration of isopulegol (100 mg/kg b.w) for 28 days signiﬁcantly restored lipid levels in plasma and liver tissue by modulating adipokine secretion in diabetic treated rats. From this we conclude that isopulegol exhibited significant antihyperlipidemic effect in HFD/STZ induced diabetic rats. Keywords: Dyslipidemia, Diabetes mellitus, Adiponectin, Leptin, PPARγ, SREBP-1C

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Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol

Cited by 131 publications

References 69 publications

Post-translational control of the long and winding road to cholesterol

Post-translational control of the long and winding road to cholesterol

Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing

Isopulegol Ameliorates Dyslipidemia by Modulating Adipokine Secretion in High Fat Diet / Streptozotocin Induced Diabetic Rats

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