IN VIVO INHIBITION OF CHOLESTEROL BIOSYNTHESIS BY A MITOCHONDRIAL EXTRACT

1961 ◽  
Vol 39 (4) ◽  
pp. 747-755 ◽  
Author(s):  
B. B. Migicovsky
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Liver Mitochondria ◽  
Blood Cholesterol ◽  
Active Principle ◽  
Aqueous Extracts ◽  
Inhibitory Substance ◽  
Cholesterol Levels ◽  
Mitochondrial Extract

Aqueous extracts of liver mitochondria were administered to rats by intraperitoneal, subcutaneous, and oral routes, and C14-acetate or mevalonate was injected intraperitoneally 3 hours later. Cholesterol synthesis in vivo from C14-acetate was depressed by the inhibitory substance in the mitochondrial extracts. Synthesis from C14-mevalonate was not inhibited.Active extracts were prepared from livers of rat, rabbit, pig, and sheep. An inhibitory substance is present in blood serum and administration of active mitochondrial extracts depressed blood cholesterol levels. Pending its identification, the active principle has been provisionally termed I.C.S. (inhibitor of cholesterol synthesis).

INHIBITION OF CHOLESTEROL BIOSYNTHESIS BY A MITOCHONDRIAL EXTRACT

1960 ◽  
Vol 38 (4) ◽  
pp. 339-346 ◽  
Author(s):  
B. B. Migicovsky
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Inhibitory Effect ◽  
Homeostatic Mechanism ◽  
Heat Labile ◽  
Mitochondrial Extract

Cholesterol biosynthesis was effectively inhibited by an extract of mitochondria disrupted with sonic oscillations. The inhibitory effect occurred both in vivo and in vitro. The inhibitor substance was heat-labile, and could be prepared from mitochondria from livers of normal or starved rats. The inhibition appeared to be of the competitive type. The locus of the inhibition in the chain of reactions from acetate to cholesterol appeared to be between acetoacetate and mevalonate. It is suggested that the inhibitor substance present in the mitochondrion represents, in part, the homeostatic mechanism that controls cholesterol synthesis by the liver.

Agents affecting lipid metabolism. XXXI. Properties of an inhibitor of cholesterol synthesis present in rabbit liver mitochondria

1968 ◽  
Vol 46 (2) ◽  
pp. 179-187 ◽  
Author(s):  
M. N. Cayen ◽  
D. Dvornik
Keyword(s):  
Cholesterol Synthesis ◽  
Liver Mitochondria ◽  
Aqueous Extracts ◽  
Hepatic Cholesterol ◽  
Large Molecules ◽  
Hepatic Cholesterol Synthesis ◽  
Significant Enrichment ◽  
Liver Homogenates ◽  
Mitochondrial Extract

Aqueous extracts of mitochondria from livers of starved animals have been reported to inhibit hepatic cholesterol synthesis. Some properties of a mitochondrial extract prepared from starved rabbits have been studied. The extract depressed the incorporation of both 2-14C-acetate and 3H-mevalonate into cholesterol by rat liver homogenates, giving concentration–dependent responses. The active factor was unstable to heat, but stable under in vitro incubation conditions, to pH changes, and to storage in the dark and cold. It was cationic and associated with one or more large molecules (mol. wt. 50 000–150 000); it was not cleaved by trypsin digestion. Fractionation experiments did not result in any significant enrichment of inhibitory activity.

FURTHER STUDIES WITH THE MITOCHONDRIAL INHIBITOR OF CHOLESTEROL SYNTHESIS

1964 ◽  
Vol 42 (1) ◽  
pp. 105-110 ◽  
Author(s):  
B. B. Migicovsky
Keyword(s):  
Aqueous Extract ◽  
Inhibitory Activity ◽  
Protein Fraction ◽  
Cholesterol Synthesis ◽  
Liver Homogenate ◽  
Liver Mitochondria ◽  
Active Principle ◽  
Mitochondrial Extract ◽  
Mitochondrial Inhibitor

The inhibitory activity of an aqueous extract of liver mitochondria (I.C.S.) was observed with Triton-treated rats. Fractionation of I.C.S. on Sephadex indicated that the active principle comes off the Sephadex with the protein fraction. Inhibitory activity was shown to be present in the 100,000 × g supernate of the liver homogenate of a starved rat, indicating that the active principle moves from the mitochondrion to the surrounding cytoplasm.Electrodialysis of the mitochondrial extract revealed that the inhibitor is permeable and moves to the cathode. The electrodialyzed material was found to be active as an inhibitor of cholesterol synthesis in vitro and in vivo.It is concluded that the active principle is associated with protein and may be separated therefrom by electrodialysis.

INHIBITION OF CHOLESTEROL BIOSYNTHESIS BY A MITOCHONDRIAL EXTRACT

1960 ◽  
Vol 38 (1) ◽  
pp. 339-346 ◽  
Author(s):  
B. B. Migicovsky
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Inhibitory Effect ◽  
Homeostatic Mechanism ◽  
Heat Labile ◽  
Mitochondrial Extract

Cholesterol biosynthesis was effectively inhibited by an extract of mitochondria disrupted with sonic oscillations. The inhibitory effect occurred both in vivo and in vitro. The inhibitor substance was heat-labile, and could be prepared from mitochondria from livers of normal or starved rats. The inhibition appeared to be of the competitive type. The locus of the inhibition in the chain of reactions from acetate to cholesterol appeared to be between acetoacetate and mevalonate. It is suggested that the inhibitor substance present in the mitochondrion represents, in part, the homeostatic mechanism that controls cholesterol synthesis by the liver.

Agents affecting lipid metabolism. XXXII. Effect of a liver mitochondrial extract on cholesterol synthesis in the rat

1968 ◽  
Vol 46 (2) ◽  
pp. 189-191
Author(s):  
M. N. Cayen ◽  
P. Hill ◽  
D. Dvornik
Keyword(s):  
Body Weight ◽  
Lipid Metabolism ◽  
Crude Extract ◽  
Cholesterol Synthesis ◽  
Liver Mitochondria ◽  
Liver Cholesterol ◽  
Acetate Incorporation ◽  
Hepatic Cholesterol ◽  
Experimental Conditions ◽  
Mitochondrial Extract

A lyophilized extract was prepared from liver mitochondria of rabbits starved for 24 h. Rats were fed single oral (1–4 g/kg body weight) and intraperitoneal (1.5 g/kg) doses of the crude extract. After 3 h, the livers of one group were removed and 2-14C-acetate incorporation into cholesterol was measured. In the second group, rats received an interperitoneal dose of 2-14C-acetate 1 h after administration of the mitochondrial extract; animals were sacrificed 2 h later and the incorporation into hepatic cholesterol was measured. Under these experimental conditions, administration of the mitochondrial extract did not decrease the incorporation of 2-14C-acetate into liver cholesterol.

scholarly journals Effect of 26-Oxygenosterols from Ganoderma lucidum and Their Activity as Cholesterol Synthesis Inhibitors

2005 ◽  
Vol 71 (7) ◽  
pp. 3653-3658 ◽  
Author(s):  
Hassan Hajjaj ◽  
Catherine Macé ◽  
Matthew Roberts ◽  
Peter Niederberger ◽  
Laurent B. Fay
Keyword(s):  
Ganoderma Lucidum ◽  
Cholesterol Synthesis ◽  
Biological Effects ◽  
Cholesterol Biosynthesis ◽  
Blood Cholesterol ◽  
Ganoderic Acid ◽  
Isolation And Identification ◽  
Medicinal Fungus ◽  
Lower Blood Cholesterol

ABSTRACT Ganoderma lucidum is a medicinal fungus belonging to the Polyporaceae family which has long been known in Japan as Reishi and has been used extensively in traditional Chinese medicine. We report the isolation and identification of the 26-oxygenosterols ganoderol A, ganoderol B, ganoderal A, and ganoderic acid Y and their biological effects on cholesterol synthesis in a human hepatic cell line in vitro. We also investigated the site of inhibition in the cholesterol synthesis pathway. We found that these oxygenated sterols from G. lucidum inhibited cholesterol biosynthesis via conversion of acetate or mevalonate as a precursor of cholesterol. By incorporation of 24,25-dihydro-[24,25-3H2]lanosterol and [3-3H]lathosterol in the presence of ganoderol A, we determined that the point of inhibition of cholesterol synthesis is between lanosterol and lathosterol. These results demonstrate that the lanosterol 14α-demethylase, which converts 24,25-dihydrolanosterol to cholesterol, can be inhibited by the 26-oxygenosterols from G. lucidum. These 26-oxygenosterols could lead to novel therapeutic agents that lower blood cholesterol.

scholarly journals MYC Enhances Cholesterol Biosynthesis and Supports Cell Proliferation Through SQLE

2021 ◽  
Vol 9 ◽  
Author(s):  
Fan Yang ◽  
Junjie Kou ◽  
Zizhao Liu ◽  
Wei Li ◽  
Wenjing Du
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Cholesterol Synthesis ◽  
Cholesterol Metabolism ◽  
Cell Metabolism ◽  
Cholesterol Biosynthesis ◽  
Potential Therapeutic Target ◽  
Cholesterol Levels ◽  
Membrane Components ◽  
Rate Limiting

Oncogene c-Myc (referred in this report as MYC) promotes tumorigenesis in multiple human cancers. MYC regulates numerous cellular programs involved in cell growth and cell metabolism. Tumor cells exhibit obligatory dependence on cholesterol metabolism, which provides essential membrane components and metabolites to support cell growth. To date, how cholesterol biosynthesis is delicately regulated to promote tumorigenesis remains unclear. Here, we show that MYC enhances cholesterol biosynthesis and promotes cell proliferation. Through transcriptional upregulation of SQLE, a rate-limiting enzyme in cholesterol synthesis pathway, MYC increases cholesterol production and promotes tumor cell growth. SQLE overexpression restores the cellular cholesterol levels in MYC-knockdown cells. More importantly, in SQLE-depleted cells, enforced expression of MYC has no effect on cholesterol levels. Therefore, our findings reveal that SQLE is critical for MYC-mediated cholesterol synthesis, and further demonstrate that SQLE may be a potential therapeutic target in MYC-amplified cancers.

scholarly journals Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas

Blood ◽  
2021 ◽  
Author(s):  
Yajie Shen ◽  
Jingqi Zhou ◽  
Kui Nie ◽  
Shuhua Cheng ◽  
Zhengming Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
B Cell Lymphomas ◽  
Tumor Load ◽  
Large B Cell

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCL.

scholarly journals Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

2021 ◽  
Vol 118 (33) ◽  
pp. e2102191118
Author(s):  
Hao Wang ◽  
Joshua A. Kulas ◽  
Chao Wang ◽  
David M. Holtzman ◽  
Heather A. Ferris ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Cholesterol Synthesis ◽  
Amyloid Β ◽  
Cholesterol Transport ◽  
Targeted Deletion ◽  
Superresolution Imaging ◽  
Cholesterol Levels ◽  
Aβ Production

Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.

scholarly journals TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination

2021 ◽  
Vol 220 (9) ◽  
Author(s):  
Wan Yun Ho ◽  
Jer-Cherng Chang ◽  
Kenneth Lim ◽  
Amaury Cazenave-Gassiot ◽  
Aivi T. Nguyen ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Cholesterol Levels ◽  
The Central Nervous System ◽  
Cholesterol Supplementation ◽  
Regulated Gene Expression ◽  
Lateral Sclerosis

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43–mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies–related diseases.

Sign in / Sign up

Export Citation Format

Share Document