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Influence of Lipid Metabolism

  • Philippe Boucher
  • Hans Gerhard Vogel
Living reference work entry

Abstract

Elevated lipid levels, especially hypercholesterolemia, result from increased absorption from the gut, enhanced endogenous synthesis, or inadequate clearance from serum. Therefore, there are three feasible ways to reduce hyperlipidemia: to block endogenous synthesis, decrease absorption, or enhance clearance from serum. These three factors can be evaluated in normal animals without artificial diets. Clinically used lipid-lowering compounds such as PPARα agonists (fibrates), cholesterol absorption inhibitors (ezetimibe), bile acid sequestrants, and HMG-CoA reductase inhibitors (statins) can be tested in this way, and their pharmacological activity further investigated with additional tests. For the investigation of the effects on plasma lipids, the right animal model has to be chosen. For fibrates, rats and mice are appropriate models; for LDL-lowering compounds, hamster, guinea, and rabbits. Earlier attempts to interfere with endogenous cholesterol synthesis resulted in the accumulation of sterols other than cholesterol (Holmes 1964). To date, only the inhibition of cholesterol biosynthesis with HMG-CoA reductase inhibitors has been a clinically effective approach for LDL cholesterol lowering (Ridker 2014). Inhibition of other enzymes of the cholesterol biosynthesis pathway upstream from HMG-CoA reductase, such as squalene synthetase were investigated by several pharmaceutical companies until the 1990s, but this development was discontinued for safety reasons. Inhibition of cholesterol biosynthesis upstream from HMG-CoA reductase leads to nonphysiological accumulation of metabolic intermediates. In the past, the inhibition of cholesterol absorption by ACAT-inhibitors was a widely followed approach. ACAT-inhibitors inhibit cholesterol absorption in rodents effectively, but so far all ACAT-inhibitors have been ineffective in humans (Farese 2006). The only compound that is effective in humans is ezetimibe, an azetidinone. The compound was discovered fortuitously in an ACAT-inhibitor program. During the development of that compound, it was found that ezetimibe inhibits cholesterol absorption independently from ACAT (Van Heek et al. 2000, 2001, 2003; Harris et al. 2003; Clader 2004). Ezetimibe inhibits cholesterol absorption in several animal models and is effective against plasma LDL cholesterol in humans (Couture and Lamarche 2013). Another approach to enhance hepatic LDL clearance is to interrupt bile acid recirculation. Compounds that inhibit bile acid absorption increase the conversion of cholesterol into bile acids, enhance hepatic clearance, and lower LDL cholesterol by LDL receptor upregulation in the liver.

Keywords

Bile Acid Syrian Hamster Fast Protein Liquid Chromatography Tris Buffer Solution Hypolipidemic Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

General Considerations

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Copyright information

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Authors and Affiliations

  1. 1.Department of PhysiologyUniversité de Strasbourg, UMR CNRS 7213Illkirch CedexFrance
  2. 2.Johann Wolfgang Goethe-Universität Frankfurt am MainFrankfurt am MainGermany

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