Mechanisms of Lipid-Lowering Agents

Sirtori, Cesare R.; Manzoni, Cristina; Lovati, Maria Rosa

doi:10.1159/000174789

Cited by 20 publications

(4 citation statements)

References 20 publications

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“…The effect of hypolipidaemic drugs seen in our cell model is less pronounced than in rat liver but stronger in the rat cell line MH1C1 than in the human cell line HepG2, but is in accordance with previous findings of Graham et al (20) in primates and of Hanefeld et al (35) in humans which indicates that the peroxisomal proliferation in human and primate is not as pronounced as in rat, although the lipid lowering effect is present in human (5). The hypotriglyceridaemic action of the se drugs is reported to be due to the decrease of apolipoprotein C-III gene expression, which was demonstrated by Staels et al (36) in rat and human hepatocytes.…”

Section: Discussionsupporting

confidence: 93%

Differential Induction of Peroxisomal Enzymes by Hypolipidaemics in Human (HepG2) and Rat (MH1C1) Hepatoma Cell Lines

Stangl

Kovacs²,

Böck³

et al. 1995

CCLM

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Dedicated to Professor Dr. Erich Kaiser on the occasion of his 70th birthdaySummary: Human (HepG2) and rat (MH1C1) hepatoblastoma cells were incubated with different concentrations of the hypolipidaemics cetaben, clofibrate and thyroxine. The enzymatic activities of catalase, peroxisomal bifunctional enzyme, succinate dehydrogenase, and 3-oxoacyl-CoA thiolase were measured. In order to determine the point of regulation of the enzymatic activities Northern and Slot blot experiments with probes for peroxisomal bifunctional enzyme, catalase and fatty acyl CoA oxidase were performed on total RNA. Catalase activity was enhanced in HepG2 cells treated with 3 rrimol/1 clofibric acid to 135% of control and the mRNA value to 2.6 fold, whereas in cetaben treated cells the enhancement (up to 119% of control) was less pronounced. In MH1C1 cells catalase activity was not changed by any of the drugs. The activity of the peroxisomal bifunctional enzyme was not affected in HepG2 cells by clofibric acid and cetaben, whereas the mRNA level was elevated to 2.3 fold by 10 μτηοΐ/l cetaben. At high concentrations of cetaben all enzyme activities were decreased in both cell lines due to its high cytotoxicity. Our data show that, due to the differences in the genomic organisation, the regulation of the enzyme activities is different in human and rat, but the results from the human and rat hepatoblastoma cells correlate with the findings in whole man and rat, so that a human in vitro system is more suitable for pharmacological tests. These results suggest that the human hepatoma cell line HepG2 may be a useful model system for studies of the influence of hypolipidaemics on the peroxisomal enzyme system.

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Section: Discussionsupporting

confidence: 93%

Differential Induction of Peroxisomal Enzymes by Hypolipidaemics in Human (HepG2) and Rat (MH1C1) Hepatoma Cell Lines

Stangl

Kovacs²,

Böck³

et al. 1995

CCLM

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“…Fibric acid derivatives are a well known group of hypolipidaemic drugs used mainly in the treatment of hypertriglyceridaemia and mixed hyperlipidaemia (Sirtori et al, 1991;Klosiewicz-Latoszek & Szostak, 1991). Although they have been in therapeutic use for more than twenty years, the mechanism(s) by which they reduce blood lipis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Relationship between plasma lipids and palmitoyl‐CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates

Alegret¹,

Ferrando²,

Vázquez³

et al. 1994

British J Pharmacology

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1 The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-CoA hydrolase and synthetase activities, as well as the correlations with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2 The administration of the three drugs caused a significant reduction in body weight gain, accompanied with a paradoxical increase in food intake in groups treated with BFB and GFB. 3 Drug treatment produced gross hepatomegaly and increase in peroxisomal a-oxidation, and these parameters were strongly correlated. The order of potency was BFB> CFB> GFB. 4 Both plasma cholesterol (BFB t CFB > GFB) and triglyceride (BFB t GFB > CFB) levels were reduced in treated animals. There was an inverse correlation between these parameters and peroxisomal P-oxidation, although the peroxisomal proliferation seemed to explain only a small part of the hypolipidemic effect observed. 5 Cytosolic and microsomal (but not mitochondrial) palmitoyl-CoA hydrolase activities were increased by the three drugs (BFB > CFB> GFB), probably by inducing the hydrolase I isoform, which is insensitive to inhibition by fibrates in vitro. The increased hydrolase activities were directly and strongly correlated with peroxisomal 0-oxidation. 6 Palmitoyl-CoA synthetase activity was also increased by the treatment with fibrates (BFB> CFB > GFB), probably as a consequence of the enhancement of hydrolase activities. 7 Some of the effects of fibrate treatment can be explained, at least in part, in terms of peroxisomal induction and caution should be exercised in the extrapolation of these results to species, such as man, that are insensitive to peroxisomal proliferation.

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“…Even though the metabolism of BS was described 45 years ago [80], the detailed metabolic turnover, absolute oral bioavailability, clearance, and volume of distribution for BS measured in healthy subjects have been reported only recently [75]. Generally, it has been considered that BS interrupts the recirculation of bile acids and/or reduces the absorption of cholesterol in the gut [81,82,83,84,85]. However, substantial experimental evidence is needed to propose the primary molecular mechanism about the physicochemical competition between cholesterol and BS and other phytosterols for micellar incorporation and uptake at the gut lumen [86].…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Critical Analysis on Characterization, Systemic Effect, and Therapeutic Potential of Beta-Sitosterol: A Plant-Derived Orphan Phytosterol

et al. 2016

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Beta-sitosterol (BS) is a phytosterol, widely distributed throughout the plant kingdom and known to be involved in the stabilization of cell membranes. To compile the sources, physical and chemical properties, spectral and chromatographic analytical methods, synthesis, systemic effects, pharmacokinetics, therapeutic potentials, toxicity, drug delivery and finally, to suggest future research with BS, classical as well as on-line literature were studied. Classical literature includes classical books on ethnomedicine and phytochemistry, and the electronic search included Pubmed, SciFinder, Scopus, the Web of Science, Google Scholar, and others. BS could be obtained from different plants, but the total biosynthetic pathway, as well as its exact physiological and structural function in plants, have not been fully understood. Different pharmacological effects have been studied, but most of the mechanisms of action have not been studied in detail. Clinical trials with BS have shown beneficial effects in different diseases, but long-term study results are not available. These have contributed to its current status as an “orphan phytosterol”. Therefore, extensive research regarding its effect at cellular and molecular level in humans as well as addressing the claims made by commercial manufacturers such as the cholesterol lowering ability, immunological activity etc. are highly recommended.

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Mechanisms of Lipid-Lowering Agents

Cited by 20 publications

References 20 publications

Differential Induction of Peroxisomal Enzymes by Hypolipidaemics in Human (HepG2) and Rat (MH1C1) Hepatoma Cell Lines

Differential Induction of Peroxisomal Enzymes by Hypolipidaemics in Human (HepG2) and Rat (MH1C1) Hepatoma Cell Lines

Relationship between plasma lipids and palmitoyl‐CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates

Critical Analysis on Characterization, Systemic Effect, and Therapeutic Potential of Beta-Sitosterol: A Plant-Derived Orphan Phytosterol

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