Sterol-independent Regulation of 3-Hydroxy-3-methylglutaryl-CoA Reductase by Mevalonate in Chinese Hamster Ovary Cells

Panini, S R; Schnitzer-Polokoff, Robin; Spencer, Thomas A.; Sinensky, Michael

doi:10.1016/s0021-9258(18)60424-7

Cited by 41 publications

(5 citation statements)

References 33 publications

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“…1) are arrested at the GUS interface of the cell cycle (163)(164)(165); this arrest is reversed with mevalonate but not with cholesterol supplements (163)(164)(165)(166)(167). Among the regulation-related events occurring prior to the onset of the S phase is the enhanced synthesis of HMG CoA reductase (163, which is resistant to sterol feedback regulation (168). Asynchronous (167) and synchronous (163-165) cells arrested at the GUS interface of the cell cycle exhibit an altered morphology.…”

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confidence: 99%

“…A sterol feedback-resistant HMG CoA reductase activity induced during the GI phase of the cell cycle (165,168) ensures a pool of farnesyl pyrophosphate, the rate-limiting substrate for the post-translational modification of the carboxyl-terminal cysteine in the CaaX sequence of neosynthesized prelamin A and lamin B (145,149,150,195,196). This covalent modification is essential to the nuclear localization of the lamins, the structural and functional integrity of the nuclear lamina, S-phase DNA synthesis, and the formation of nuclear envelopes in daughter cells following completion of mitosis (147,149).…”

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confidence: 99%

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Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

Elson

Peffley

Hentosh

et al. 1999

Experimental Biology and Medicine

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Pure and mixed isoprenoid end products of plant mevalonate metabolism trigger actions that suppress 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. These actions modulate HMG CoA reductase mRNA translation and the proteolytic degradation of HMG CoA reductase. Such post-transcriptional events, we propose, are activated directly by acyclic isoprenoids and indirectly by cyclic isoprenoids. Isoprenoids, acting secondarily to the dominant transcriptional effector of sterologenesis, modestly lower cholesterol levels, if and only if, sterologenesis is not repressed by a saturating imput of dietary cholesterol. An anomaly associated with tumor growth-a sterol feedback-resistant HMG CoA reductase activityensures a pool of sterologenic pathway intermediates. Such intermediates provide lipophilic anchors essential for membrane attachment and biological activity of growth hormone receptors, nuclear lamins A and B, and oncogenic ras. Tumor HMG CoA reductase retains high sensitivity to the isoprenoid-mediated secondary regulation. Repression of mevalonate synthesis by plant-derived isoprenoids reduces ras and lamin B processing, arrests cells in G1, and initiates cellular apoptosis. This unique tumor cell-specific sensitivity allows isoprenoids to be used for tumor therapy, an application emulating that of the statins, but one free of adverse effects. When evaluated at levels provided by a typical diet, isoprenoids individually have no impact on cholesterol synthesis and tumor growth. Nonetheless, isoprenoid-mediated activities are additive, and, sometimes synergistic. Therefore, the combined actions of the estimated 23,000 isoprenoid constituents of plant materials, acting in concert with other chemopreventive phytochemicals, may explain the lowered cancer risk associated with a diet rich in plant products. In contrast, that lowering of cancer risk does not correspond to supplemental intake of other dietary factors associated with fruits, vegetables, and cereal grains, namely fiber, p-carotene, vitamin C, and vitamin E, and only weakly to supplemental folate.

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confidence: 99%

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confidence: 99%

Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

Elson

Peffley

Hentosh

et al. 1999

Experimental Biology and Medicine

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“…HMGCR catalyzed by acetyl-CoA is a membrane-bound glycoprotein consisting of 888 amino acids and it acts on the mevalonate pathway, which is the initial control point for endogenous cholesterol biosynthesis. HMGCR activity and quantity are regulated by cholesterol biosynthesis through several mechanisms, including negative feedback regulation mechanisms derived from mevalonate-induced sterol and nonsterol metabolite [ 18 ], HMGCR mRNA synthesis [ 19 ], HMGCR protein degradation [ 20 ], hormonal regulation [ 21 ], and gene regulation and genetic diversity [ 22 ]. These mechanisms interact to regulate cholesterol homeostasis.…”

Section: Hmgcr-induced Cholesterol Synthesis Mechanismmentioning

confidence: 99%

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Zhou,

Wu,

Wang

et al. 2023

IJMS

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Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.

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“…HMG-CoA reductase assay. HMG-CoA reductase was assayed essentially according to previous procedures (2,32,33). The samples were preincubated for 30 min at 37 Њ C before the addition of substrate to ensure the inactivation of HMG-CoA lyase activity (2) The samples were centrifuged and 100 l of the protein-free samples was spotted on TLC plates and developed in benzene-acetone 1:1 (v/v) (32).…”

Section: Enzyme Assaysmentioning

confidence: 99%

Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism

Gupta

Mehan

Tansey

et al. 1999

Journal of Lipid Research

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Sterol-independent Regulation of 3-Hydroxy-3-methylglutaryl-CoA Reductase by Mevalonate in Chinese Hamster Ovary Cells

Cited by 41 publications

References 33 publications

Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

Isoprenoid-Mediated Inhibition of Mevalonate Synthesis: Potential Application to Cancer

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism

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