Regulation of early cholesterol biosynthesis in rat liver: Effects of sterols, bile acids, lovastatin, and BM 15.766 on 3-hydroxy-3-methylglutaryl coenzyme A synthase and acetoacetyl coenzyme A thiolase activities

Authors

  • Akira Honda 385 Tremont Ave.,

    Corresponding author
    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
    • East Orange, NJ 07018-1095. Fax: (973) 676-2991
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  • Gerald Salen,

    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
    2. Veterans Affairs Medical Center, East Orange, NJ
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  • Lien B. Nguyen,

    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
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  • Guorong Xu,

    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
    2. Veterans Affairs Medical Center, East Orange, NJ
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  • G. Stephen Tint,

    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
    2. Veterans Affairs Medical Center, East Orange, NJ
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  • Ashok K. Batta,

    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
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  • Sarah Shefer

    1. Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ
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Abstract

Cytosolic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase catalyzes the formation of HMG-CoA, the substrate for the rate-controlling enzyme in the cholesterol biosynthetic pathway. To explore the regulation in liver, we developed a new, accurate, and reliable reversed-phase ion-pair chromatographic assay that uses nonradioactive substrates and n-propionyl coenzyme A as an internal recovery standard. The hepatic activities were measured in rats treated with cholesterol, sitosterol, cholic acid, deoxycholic acid, ursodeoxycholic acid, cholestyramine, bile fistula, lovastatin, and BM 15.766, an inhibitor of 7-dehydrocholesterol Δ7-reductase, and were compared with microsomal HMG-CoA reductase and cytosolic acetoacetyl coenzyme A (AcAc-CoA) thiolase activities. HMG-CoA synthase activity was effectively suppressed in synchrony with HMG-CoA reductase activity by treatments with cholesterol (−41%, P< .05), cholic acid (−72%, P< .005), and deoxycholic acid (−62%, P< .05). However, ursodeoxycholic acid increased activity 84% (P< .05) and intravenous sitosterol did not change activity. AcAc-CoA thiolase activities also paralleled HMG-CoA reductase and HMG-CoA synthase activities, but differences were not statistically significant. In contrast to inhibition, up-regulation of hepatic HMG-CoA synthase activities by cholestyramine, bile fistula, and lovastatin was much less than HMG-CoA reductase activities. In addition, BM 15.766 did not stimulate synthase activity, whereas lovastatin increased activity 2.4-fold. Thus, hepatic HMG-CoA synthase activity was regulated coordinately with HMG-CoA reductase, and responded more forcefully to regulatory stimuli than acetoacetyl-CoA thiolase activity but usually less than HMG-CoA reductase.

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