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Inhibition of Cholesterol Biosynthesis - Springer

Furthermore, thisinhibition appears to occur at the stage of cholesterol biosynthesis atwhich mevalonate is decarboxylated.

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Inhibition of cholesterol biosynthesis by cholic acid.

N2 - Cholesterol has several important physiological functions in mammals and is also indispensable during embryogenesis. Genetic defects of the cholesterol biosynthetic pathway lead to different inborn errors. The phenotypic abnormalities are caused by cholesterol deficiency and accumulation of intermediate sterols. Lanosterol 14α-demethylase (CYP51) catalyses the first step following cyclization of squalene in cholesterol biosynthesis. CYP51 requires cytochrome P450 oxidoreductase (POR) that is the obligate electron donor for the reaction. Some patients with Antley-Bixler syndrome have mutations in the POR gene. A similar phenotype was also observed after early in utero exposure to azoles, which are inhibitors of fungal CYP51 used to treat systemic mycoses. The reason in both cases might be the inhibition of cholesterol biosynthesis on the level of CYP51. The aim of our work was to determine the effect of cytochrome P450-oxidoreductase on cholesterol biosynthesis in liver. We used HPLC analysis to profile sterols in the liver of wild mice and liver specific Por knock-out mice. We show that Por deletion caused strong accumulation of lanosterol. We observed 35-fold induction compared to wild type (397 μg/g vs. 11 μg/g). Despite the build up of lanosterol, the amount of total liver cholesterol did not change. Our results confirm POR as an obligate and unchangeable electron donor for CYP51 mediated reaction. POR deficiency inhibits lanosterol conversion to FF-MAS as well as cholesterol biosynthesis de novo. Homeostatic mechanisms are able to regulate cholesterol level, most probably through uptake of exogenous cholesterol from diet.

Inhibition of Cholesterol Biosynthesis | SpringerLink

Our results suggest thathypoxia inhibits cholesterol biosynthesis by suppressing SREBP1a-regulated gene expression and this suppression is caused by the blockage of SREBP1abinding to SRE sequence by HIF-1.

Feedback Inhibition of Cholesterol Biosynthesis by …

Figure 3. Chemical structures for reduction reaction of 3-hydroxy-3-methylglutaryl-CoA, better known as HMG-CoA, into mevalonate as catalyzed by HMG-CoA reductase. HMG-CoA is the substrate for HMGR, a key enzyme that catalyzes this committed step in the cholesterol biosynthesis pathway. Statins seek to suppress this pathway by out-competing HMG-CoA for binding in the active site of HMGR (adapted from reference 1).

The biosynthesis of cholesterol in the liver and intestinal cells is a process that creates the essential lipid from acetyl CoA subunits. Much interaction and regulation exists between this endogenous synthesis process and the absorption of dietary cholesterol in the small intestine. As less cholesterol is consumed, synthesis increases in order to meet the body’s demands for the nutrient, while an increase in consumption results in the downregulation of the endogenous process (2). Canonically, the synthesis pathway is divided into three distinct segments: the synthesis of activated isoprene subunits, the condensation of these isoprene molecules to form squalene, and squalene’s cyclization into cholesterol (3) The cholesterol synthesis pathway, as divided into the three main steps listed above, is shown below (Fig. 4).

Mechanism of the inhibition of cholesterol biosynthesis …

Cholesterol has several important physiological functions in mammals and is also indispensable during embryogenesis. Genetic defects of the cholesterol biosynthetic pathway lead to different inborn errors. The phenotypic abnormalities are caused by cholesterol deficiency and accumulation of intermediate sterols. Lanosterol 14α-demethylase (CYP51) catalyses the first step following cyclization of squalene in cholesterol biosynthesis. CYP51 requires cytochrome P450 oxidoreductase (POR) that is the obligate electron donor for the reaction. Some patients with Antley-Bixler syndrome have mutations in the POR gene. A similar phenotype was also observed after early in utero exposure to azoles, which are inhibitors of fungal CYP51 used to treat systemic mycoses. The reason in both cases might be the inhibition of cholesterol biosynthesis on the level of CYP51. The aim of our work was to determine the effect of cytochrome P450-oxidoreductase on cholesterol biosynthesis in liver. We used HPLC analysis to profile sterols in the liver of wild mice and liver specific Por knock-out mice. We show that Por deletion caused strong accumulation of lanosterol. We observed 35-fold induction compared to wild type (397 μg/g vs. 11 μg/g). Despite the build up of lanosterol, the amount of total liver cholesterol did not change. Our results confirm POR as an obligate and unchangeable electron donor for CYP51 mediated reaction. POR deficiency inhibits lanosterol conversion to FF-MAS as well as cholesterol biosynthesis de novo. Homeostatic mechanisms are able to regulate cholesterol level, most probably through uptake of exogenous cholesterol from diet.

The synthesis of mevalonate from HMG-CoA, which occurs during the first segment of the pathway, is regarded as the “committed step” in cholesterol biosynthesis (Fig. 3). For this reason, much of the regulation that controls this process targets the enzyme responsible for this conversion; HMGR (3). HMGR is controlled through a variety of mechanisms to ensure that proper levels of cholesterol are maintained throughout the body. This array of methods includes the ubiquitination and subsequent degradation of the enzyme complex in the endoplasmic reticulum, inactivation via phosphorylation, or prevention of the transcription and translation of the enzyme and its mRNA (4). The importance of this enzyme and the reaction it catalyzes to the entire process of cholesterol biosynthesis makes inhibition of HMGR a rational and effective target for drugs that seek to lower blood cholesterol. By blocking the committed step of cholesterol biosynthesis, statins reduce the amount of cholesterol synthesized in a similar manner as that employed endogenously.

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  • Inhibition of cholesterol biosynthesis under hypoxia

    Feedback Inhibition of Cholesterol Biosynthesis by Dietary Cholesterol in Experimental Chronic Renal Failure

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    The Herbicide Linuron Inhibits Cholesterol Biosynthesis and Induces Cellular Stress Responses in Brown Trout

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    Inhibition of Cholesterol Biosynthesis by Triparanol in Rheumatoid Arthritis

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cholesterol biosynthesis - The Medical Biochemistry Page

T1 - Inhibition of cholesterol biosynthesis in Chinese hamster ovary cells by 4,4,10β-trimethyl-trans-decal-3β-ol. A specific 2,3-oxidosqualene cyclase inhibitor

Cholesterol Sulfate Deficiency and Coronary Heart …

AB - Cholesterol has several important physiological functions in mammals and is also indispensable during embryogenesis. Genetic defects of the cholesterol biosynthetic pathway lead to different inborn errors. The phenotypic abnormalities are caused by cholesterol deficiency and accumulation of intermediate sterols. Lanosterol 14α-demethylase (CYP51) catalyses the first step following cyclization of squalene in cholesterol biosynthesis. CYP51 requires cytochrome P450 oxidoreductase (POR) that is the obligate electron donor for the reaction. Some patients with Antley-Bixler syndrome have mutations in the POR gene. A similar phenotype was also observed after early in utero exposure to azoles, which are inhibitors of fungal CYP51 used to treat systemic mycoses. The reason in both cases might be the inhibition of cholesterol biosynthesis on the level of CYP51. The aim of our work was to determine the effect of cytochrome P450-oxidoreductase on cholesterol biosynthesis in liver. We used HPLC analysis to profile sterols in the liver of wild mice and liver specific Por knock-out mice. We show that Por deletion caused strong accumulation of lanosterol. We observed 35-fold induction compared to wild type (397 μg/g vs. 11 μg/g). Despite the build up of lanosterol, the amount of total liver cholesterol did not change. Our results confirm POR as an obligate and unchangeable electron donor for CYP51 mediated reaction. POR deficiency inhibits lanosterol conversion to FF-MAS as well as cholesterol biosynthesis de novo. Homeostatic mechanisms are able to regulate cholesterol level, most probably through uptake of exogenous cholesterol from diet.

Tuscany Diet - Biochemistry and Nutrition

The herbicide linuron is used worldwide, and has been detected in surface waters as well as in food and drinking water. Toxicological studies have reported that linuron acts as an antiandrogen in vitro and in vivo and disrupts mammalian male reproductive function. However, global mechanisms of linuron toxicity are poorly documented. We used RNA-seq to characterize the hepatic transcriptional response of mature male brown trout exposed for 4 days to 1.7, 15.3, and 225.9 μg/L linuron. We identified a striking decrease in the expression of transcripts encoding the majority of enzymes forming the cholesterol biosynthesis pathway. We also measured a very significant decrease in total hepatic cholesterol in fish exposed to 225.9 μg/L linuron and a negative correlation between total cholesterol and linuron treatment concentration. We hypothesize that inhibition of cholesterol biosynthesis may result from the disruption of androgen signaling by linuron. Additionally, there was increased expression of a number of transcripts involved in cellular stress responses, including (up to 560-fold), molecular chaperones, and antioxidant enzymes. We found some evidence of similar patterns of transcriptional change in fish exposed to an environmentally relevant concentration of linuron, and further research should investigate the potential for adverse effects to occur following chronic environmental exposure.

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