Stereologic Studies on Hypertrophied Liver Cells of Rats

Biphenylyl derivatives have been shown to be effective inhibitors of cholesterol biosynthesis. The administration of biphenylyl methylvaleric acid (BMVA), to rats reduces serum and liver cholesterol levels and at the same time induces liver enlargement. This hepatotrophic effect has been confirmed in recent studies, where it was demonstrated that this hepatomegaly was due to an absolute increase of the hepatic mass without changes in the liver cell population, as reflected by the diminished DNA concentration and unchanged total DNA content of the organ.Since this hepatocytic hypertrophy represents an ideal model for studying the process of drug-induced cell enlargement, the present study was aimed to determine the organelles responsible for the liver enlargement by combined light and electron microscopic stereology measurements. Groups of rats were fed 300 mg of BMVA per kg of body weight, mixed with the food.

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Effects of Thiamin Deficiency and Thiamin Antagonists on Serum and Liver Cholesterol Levels and on Cholesterol Biosynthesis in Rats

Journal of Nutrition ◽

10.1093/jn/104.12.1690 ◽

1974 ◽

Vol 104 (12) ◽

pp. 1690-1695 ◽

Cited By ~ 3

Author(s):

C. J. Gubler ◽

J. W. Peterson ◽

K. K. Turpin ◽

L. W. Crane ◽

L. G. W. Turner ◽

...

Keyword(s):

Cholesterol Biosynthesis ◽

Liver Cholesterol ◽

Thiamin Deficiency ◽

Cholesterol Levels

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Plasma cholesterol levels and liver cholesterol biosynthesis in rabbits fed commercial or semisynthetic diets with and without added fats or oils

Atherosclerosis ◽

10.1016/0021-9150(71)90007-4 ◽

1971 ◽

Vol 13 (1) ◽

pp. 67-76 ◽

Cited By ~ 27

Author(s):

K.K. Carroll

Keyword(s):

Plasma Cholesterol ◽

Cholesterol Biosynthesis ◽

Liver Cholesterol ◽

Cholesterol Levels

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Inhibition of cholesterol biosynthesis by cholic acid

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1959.197.6.1339 ◽

1959 ◽

Vol 197 (6) ◽

pp. 1339-1340 ◽

Cited By ~ 9

Author(s):

William T. Beher ◽

Gizella D. Baker

Keyword(s):

Cholic Acid ◽

Serum Cholesterol ◽

Cholesterol Biosynthesis ◽

Mevalonic Acid ◽

Incorporation Rate ◽

Liver Cholesterol ◽

Entire Series ◽

Cholesterol Levels

The effects of dietary cholic acid on free, total and ester cholesterol levels in liver and serum, and on the relative rates of incorporation of acetate-1-C14 and mevalonic acid-2-C14 were investigated in the rat. Cholic acid caused equally significant increases in free and ester liver cholesterol. No significant changes were found in serum cholesterol levels. The incorporation rate of acetate-1-C14 into liver and serum cholesterol was inhibited by 65% when cholic acid was fed to rats, while the inhibition of mevalonic acid-2-C14 incorporation was 25%. It is suggested that cholic acid inhibits cholesterol biosynthesis between mevalonic acid and cholesterol, or retards the entire series of reactions between acetate and cholesterol.

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Early Development of Drug-Induced Hepatic Necrosis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066942 ◽

1971 ◽

Vol 29 ◽

pp. 576-577

Author(s):

F. G. Zaki ◽

E. Detzi ◽

C. H. Keysser

Keyword(s):

Early Development ◽

Hepatic Necrosis ◽

Screening Tests ◽

Dense Matrix ◽

Sprague Dawley ◽

Electron Microscopic ◽

Drug Induced ◽

Hepatocellular Damage ◽

Sprague Dawley Rats ◽

Microscopic Studies

This study represents the first in a series of investigations carried out to elucidate the mechanism(s) of early hepatocellular damage induced by drugs and other related compounds. During screening tests of CNS-active compounds in rats, it has been found that daily oral administration of one of these compounds at a dose level of 40 mg. per kg. of body weight induced diffuse massive hepatic necrosis within 7 weeks in Charles River Sprague Dawley rats of both sexes. Partial hepatectomy enhanced the development of this peculiar type of necrosis (3 weeks instead of 7) while treatment with phenobarbital prior to the administration of the drug delayed the appearance of necrosis but did not reduce its severity.Electron microscopic studies revealed that early development of this liver injury (2 days after the administration of the drug) appeared in the form of small dark osmiophilic vesicles located around the bile canaliculi of all hepatocytes (Fig. 1). These structures differed from the regular microbodies or the pericanalicular multivesicular bodies. They first appeared regularly rounded with electron dense matrix bound with a single membrane. After one week on the drug, these vesicles appeared vacuolated and resembled autophagosomes which soon developed whorls of concentric lamellae or cisterns characteristic of lysosomes (Fig. 2). These lysosomes were found, later on, scattered all over the hepatocytes.

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The Effect of Oxidized Cholesterol on the Aorta of Rabbits- Scanning Electron Microscopic Observations

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100054327 ◽

1982 ◽

Vol 40 ◽

pp. 340-341

Author(s):

S. K. Pena ◽

C. B. Taylor ◽

J. Hill ◽

J. Safarik

Keyword(s):

Cholesterol Biosynthesis ◽

Cholesterol Content ◽

Arterial Injury ◽

Electron Microscopic ◽

Aortic Smooth Muscle ◽

Oxidized Cholesterol ◽

Initial Event ◽

Membrane Structure And Function ◽

Scanning Electron Microscopic ◽

And Function

Introduction: Oxidized cholesterol derivatives have been demonstrated in various cell cultures to be very potent inhibitors of 3-hvdroxy-3- methylglutaryl Coenzyme A reductase which is a principle regulator of cholesterol biosynthesis in the cell. The cholesterol content in the cells exposed to oxidized cholesterol was found to be markedly decreased. In aortic smooth muscle cells, the potency of this effect was closely related to the cytotoxicity of each derivative. Furthermore, due to the similarity of their molecular structure to that of cholesterol, these oxidized cholesterol derivatives might insert themselves into the cell membrane, alter membrane structure and function and eventually cause cell death. Arterial injury has been shown to be the initial event of atherosclerosis.

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Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00064-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Vijay R. Varma ◽

H. Büşra Lüleci ◽

Anup M. Oommen ◽

Sudhir Varma ◽

Chad T. Blackshear ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Tissue ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Homeostasis ◽

Transcriptomic Data ◽

Brain Cholesterol ◽

Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

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Impaired cholesterol metabolism in the mice model of cystic fibrosis. A vicious circle?

10.1101/2019.12.13.875336 ◽

2019 ◽

Author(s):

Felice Amato ◽

Alice Castaldo ◽

Giuseppe Castaldo ◽

Gustavo Cernera ◽

Gaetano Corso ◽

...

Keyword(s):

Cystic Fibrosis ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Absorption ◽

Vicious Circle ◽

Liver Cholesterol ◽

Mice Model ◽

Hepatic Expression ◽

Expression Of Genes ◽

Low Cholesterol

AbstractPatients with cystic fibrosis (CF) have low cholesterol absorption and, despite enhanced endogenous biosynthesis, low serum cholesterol. Herein, we investigated cholesterol metabolism in a murine CF model in comparison to wild type (WT) testing serum and liver surrogate biomarkers together with the hepatic expression of genes involved in cholesterol metabolism. CF mice display lower sterols absorption and increased endogenous biosynthesis. Subsequently, we evaluated the effects of a cholesterol-supplemented diet on cholesterol metabolism in CF and WT mice. The supplementation in WT mice determines biochemical changes similar to humans. Instead, CF mice with supplementation did not show significant changes, except for serum phytosterols (−50%), liver cholesterol (+35%) and TNFα mRNA expression, that resulted 5-fold higher than in CF without supplementation. However, liver cholesterol in CF mice with supplementation resulted significantly lower compared to WT supplemented mice. This study shows that in CF mice there is a vicious circle in which the altered bile salts synthesis/secretion contribute to reduce cholesterol digestion/absorption. The consequence is the enhanced liver cholesterol biosynthesis that accumulates in the cell triggering inflammation.

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