Treatment of Hypercholesterolemia by Interference With Bile Acid Metabolism

Abstract

Significant reductions of plasma cholesterol can be effected in most patients with hypercholesterolemia by interruption of the enterohepatic circulation of bile acids. This can be accomplished medically by the use of cholestyramine resin, or surgically by the ileal exclusion operation. Both procedures cause a block in the reabsorption of bile acids. Due to release of feedback regulation from a reduction in bile acids returning to the liver, the conversion of cholesterol into bile acids is greatly enhanced; this in turn causes a drain on body cholesterol. A decrease in the plasma cholesterol level is one consequence of this change and, in many patients, large reductions of cholesterol can be achieved. Although these approaches to the treatment of hypercholesterolemia are associated with certain gastrointestinal side effects, both cholestyramine and ileal exclusion represent promising methods for treatment of this disorder.During the past decade it has been established that inter¬ ruption of the enterohepatic circula¬ tion of bile acids causes a lowering of the plasma cholesterol level. Two ap¬ proaches are presently being used in man to block the reabsorption of bile acids in order to produce a prolonged interruption of this circulation: first, the chemical binding of bile acids in the intestinal tract; and second, the surgical exclusion of the lower third of the small intestine where bile acids are mainly reabsorbed. The recircula¬ tion of bile acids can also be com¬ pletely inhibited by biliary fistula, but this technique has not yet proven to be a practical form of therapy for man. It is the purpose of this re¬ view to compare the two former ap¬ proaches with regard to their effects on cholesterol metabolism and with special reference to their potential usefulness in the treatment of hyper¬ cholesterolemia. In this review four major areas will be examined: (1) the changes in metabolism of bile acids and cholesterol produced by inter¬ ruption of enterohepatic circulation of bile acids; (2) the relative effec¬ tiveness of the two methods for low-ering the level of plasma cholesterol;(3) the more immediate side effects observed clinically and possible ad¬ verse reactions associated with pro¬ longed treatment; and (4) the clinical applications of these techniques for the treatment of patients with ele¬ vated levels of plasma cholesterol.The possibility of lowering plasma cholesterol levels by binding bile acids in the intestinal tract was recognized by Siperstein et al1 in 1953; these workers demonstrated that ferric chloride solution given orally has a hypocholesterolemic action in choles¬ terol-fed cockerels. This agent appar¬ ently exerts its action in the intesti¬ nal tract by precipitating bile acids; this action in turn causes a reduction in the absorption of cholesterol. The toxicity of ferric chloride solution has precluded its clinical use, but the principle of this approach has found a more practical application in another agent, cholestyramine, as described by Tennent et al.2 Cholestyramine is a quaterna...

Effects of Neomycin Alone and in Combination with Cholestyramine on Serum Cholesterol and Fecal Steroids in Hypercholesterolemic Subjects

“…Neomycin decreased serum cholesterol in This study was (1,2). Cholestyramine is an unabsorbable ion exchanger that binds bile acids in the intestinal lumen so that cholesterol elimination into the stools as bile acids is enhanced, subsequent average reductions of serum cholesterol being in the range of 20 to 30% (3). Because neomycin precipitates dihydroxy bile acids in vitro (4)(5)(6)(7)(8), its cholesterol-lowering effect was also assumed to be a result of enhanced bile acid excretion into feces, particularly because earlier studies, employing relatively large doses of neomycin or Nmethylated neomycin derivative without antibiotic properties, actually demonstrated an increase in both fecal bile acids and neutral sterols (6,9,10).…”

Bile Acid Kinetics in Relation to Sex, Serum Lipids, Body Weights, and Gallbladder Disease in Patients with Various Types of Hyperlipoproteinemia

“…Treatment with this drug often results in a normalization of the type II lipoprotein pattern (33). The effect is not achieved by a reduced LDL synthesis but is associated with an increased fractional catabolic rate of the LDL protein moiety (34).…”

In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I

“…Solutions of peptides and purifi ed peptide-DMPC nanoparticles were further concentrated using Amicon centrifugal fi lters (Millipore) with 3 K and 10 K molecular weight cut-offs, respectively. Neomycin and cholestyramine were used as positive control compounds, as these compounds are known to inhibit intestinal cholesterol absorption by precipitating micellar lipids and sequestrating bile acids, respectively (41)(42)(43)(44).…”