Recent explanatory trials of the mode of action of drug therapies on lipoprotein metabolism

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    Abstract

    Purpose of review: Dysregulated lipoprotein metabolism leads to increased plasma concentrations of atherogenic lipoproteins. We highlight the findings from recent studies of the effect of lipid-regulating therapies on apolipoprotein metabolism in humans employing endogenous labelling with stable isotopically labelled isotopomers. Recent findings: Fish oil supplementation and niacin treatment both reduce fasting and postprandial triglyceride levels by decreasing the hepatic secretion of VLDL-apoB-100 (apoB) and apoB-48-containing chylomicron particles in obese and/or type 2 diabetes. Niacin also lowers plasma LDL-apoB and Lp(a) levels by increasing catabolism of LDL-apoB and decreasing secretion of Lp(a), respectively. In subjects with hypercholesterolaemia, inhibition of cholesteryl ester transfer protein raises apoA-I and lowers apoB by decreasing and increasing the catabolism of HDL-apoA-I and LDL-apoB, respectively. Antisense oligonucleotides directed at apoB mRNA lowers plasma LDL-cholesterol and apoB chiefly by increasing the catabolism and decreasing the secretion of LDL-apoB in healthy subjects. That apoB ASO treatment does not lower hepatic secretion in humans is unexpected and merits further investigation. Summary: Kinetic studies provide mechanistic insight into the mode of action of lipid lowering therapies and lipoprotein disorders. Understanding the mode of action of new drugs in vivo is important to establish their effective use in clinical practice.

    Original languageEnglish
    Pages (from-to)550-556
    Number of pages7
    JournalCurrent Opinion in Lipidology
    Volume27
    Issue number6
    DOIs
    Publication statusPublished - Dec 2016

    Fingerprint

    Apolipoproteins B
    Lipoproteins
    Drug Therapy
    Niacin
    Apolipoprotein A-I
    Apolipoprotein B-48
    Apolipoprotein B-100
    Cholesterol Ester Transfer Proteins
    Lipids
    Chylomicrons
    Fish Oils
    Apolipoproteins
    Antisense Oligonucleotides
    Liver
    Therapeutics
    Hypercholesterolemia
    LDL Cholesterol
    Type 2 Diabetes Mellitus
    Fasting
    Healthy Volunteers

    Cite this

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    title = "Recent explanatory trials of the mode of action of drug therapies on lipoprotein metabolism",
    abstract = "Purpose of review: Dysregulated lipoprotein metabolism leads to increased plasma concentrations of atherogenic lipoproteins. We highlight the findings from recent studies of the effect of lipid-regulating therapies on apolipoprotein metabolism in humans employing endogenous labelling with stable isotopically labelled isotopomers. Recent findings: Fish oil supplementation and niacin treatment both reduce fasting and postprandial triglyceride levels by decreasing the hepatic secretion of VLDL-apoB-100 (apoB) and apoB-48-containing chylomicron particles in obese and/or type 2 diabetes. Niacin also lowers plasma LDL-apoB and Lp(a) levels by increasing catabolism of LDL-apoB and decreasing secretion of Lp(a), respectively. In subjects with hypercholesterolaemia, inhibition of cholesteryl ester transfer protein raises apoA-I and lowers apoB by decreasing and increasing the catabolism of HDL-apoA-I and LDL-apoB, respectively. Antisense oligonucleotides directed at apoB mRNA lowers plasma LDL-cholesterol and apoB chiefly by increasing the catabolism and decreasing the secretion of LDL-apoB in healthy subjects. That apoB ASO treatment does not lower hepatic secretion in humans is unexpected and merits further investigation. Summary: Kinetic studies provide mechanistic insight into the mode of action of lipid lowering therapies and lipoprotein disorders. Understanding the mode of action of new drugs in vivo is important to establish their effective use in clinical practice.",
    keywords = "Cardiovascular disease, Dyslipoproteinaemia, Lipid-regulating agents, Lipoprotein metabolism, Stable isotope study",
    author = "Chan, {Dick C.} and Barrett, {P. Hugh R} and Watts, {Gerald F.}",
    year = "2016",
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    language = "English",
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    TY - JOUR

    T1 - Recent explanatory trials of the mode of action of drug therapies on lipoprotein metabolism

    AU - Chan, Dick C.

    AU - Barrett, P. Hugh R

    AU - Watts, Gerald F.

    PY - 2016/12

    Y1 - 2016/12

    N2 - Purpose of review: Dysregulated lipoprotein metabolism leads to increased plasma concentrations of atherogenic lipoproteins. We highlight the findings from recent studies of the effect of lipid-regulating therapies on apolipoprotein metabolism in humans employing endogenous labelling with stable isotopically labelled isotopomers. Recent findings: Fish oil supplementation and niacin treatment both reduce fasting and postprandial triglyceride levels by decreasing the hepatic secretion of VLDL-apoB-100 (apoB) and apoB-48-containing chylomicron particles in obese and/or type 2 diabetes. Niacin also lowers plasma LDL-apoB and Lp(a) levels by increasing catabolism of LDL-apoB and decreasing secretion of Lp(a), respectively. In subjects with hypercholesterolaemia, inhibition of cholesteryl ester transfer protein raises apoA-I and lowers apoB by decreasing and increasing the catabolism of HDL-apoA-I and LDL-apoB, respectively. Antisense oligonucleotides directed at apoB mRNA lowers plasma LDL-cholesterol and apoB chiefly by increasing the catabolism and decreasing the secretion of LDL-apoB in healthy subjects. That apoB ASO treatment does not lower hepatic secretion in humans is unexpected and merits further investigation. Summary: Kinetic studies provide mechanistic insight into the mode of action of lipid lowering therapies and lipoprotein disorders. Understanding the mode of action of new drugs in vivo is important to establish their effective use in clinical practice.

    AB - Purpose of review: Dysregulated lipoprotein metabolism leads to increased plasma concentrations of atherogenic lipoproteins. We highlight the findings from recent studies of the effect of lipid-regulating therapies on apolipoprotein metabolism in humans employing endogenous labelling with stable isotopically labelled isotopomers. Recent findings: Fish oil supplementation and niacin treatment both reduce fasting and postprandial triglyceride levels by decreasing the hepatic secretion of VLDL-apoB-100 (apoB) and apoB-48-containing chylomicron particles in obese and/or type 2 diabetes. Niacin also lowers plasma LDL-apoB and Lp(a) levels by increasing catabolism of LDL-apoB and decreasing secretion of Lp(a), respectively. In subjects with hypercholesterolaemia, inhibition of cholesteryl ester transfer protein raises apoA-I and lowers apoB by decreasing and increasing the catabolism of HDL-apoA-I and LDL-apoB, respectively. Antisense oligonucleotides directed at apoB mRNA lowers plasma LDL-cholesterol and apoB chiefly by increasing the catabolism and decreasing the secretion of LDL-apoB in healthy subjects. That apoB ASO treatment does not lower hepatic secretion in humans is unexpected and merits further investigation. Summary: Kinetic studies provide mechanistic insight into the mode of action of lipid lowering therapies and lipoprotein disorders. Understanding the mode of action of new drugs in vivo is important to establish their effective use in clinical practice.

    KW - Cardiovascular disease

    KW - Dyslipoproteinaemia

    KW - Lipid-regulating agents

    KW - Lipoprotein metabolism

    KW - Stable isotope study

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    U2 - 10.1097/MOL.0000000000000348

    DO - 10.1097/MOL.0000000000000348

    M3 - Review article

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    EP - 556

    JO - Current Opinion in Lipidology

    JF - Current Opinion in Lipidology

    SN - 0957-9672

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