Inhibition of Cholesterol Absorption: Targeting the Intestine

Abstract

Atherosclerosis, the gradual formation of a lipid-rich plaque in the arterial wall is the primary cause of Coronary Artery Disease (CAD), the leading cause of mortality worldwide. Hypercholesterolemia, elevated circulating cholesterol, was identified as a key risk factor for CAD in epidemiological studies. Since the approval of Mevacor in 1987, the primary therapeutic intervention for hypercholesterolemia has been statins, drugs that inhibit the biosynthesis of cholesterol. With improved understanding of the risks associated with elevated cholesterol levels, health agencies are recommending reductions in cholesterol that are not achievable in every patient with statins alone, underlying the need for improved combination therapies. The whole body cholesterol pool is derived from two sources, biosynthesis and diet. Although statins are effective at reducing the biosynthesis of cholesterol, they do not inhibit the absorption of cholesterol, making this an attractive target for adjunct therapies. This report summarizes the efforts to target the gastrointestinal absorption of cholesterol, with emphasis on specifically targeting the gastrointestinal tract to avoid the off-target effects sometimes associated with systemic exposure.

Corn oil improves the plasma lipoprotein lipid profile compared with extra-virgin olive oil consumption in men and women with elevated cholesterol: Results from a randomized controlled feeding trial

“…Also, absorption of sterols into enterocytes triggers upregulation of adenosine triphosphate binding cassette G5 and G8 transporters, thereby increasing the efflux of sterols into the intestinal lumen for excretion. [27][28][29] Ostlund and colleagues evaluated cholesterol absorption after a single meal test with native CO and CO stripped of phytosterols, and showed significantly greater cholesterol absorption after consumption of the phytosterol-free CO (P 5 .005). 30 Howell et al addressed the hypothesis that phytosterols in CO accounted for the differential action on lipoprotein lipids compared with OO by administering 10-day diets containing CO, olive oil, and olive oil supplemented with phytosterols at twice the level found naturally in CO to 16 normolipidemic men and women.…”

Sustained and selective suppression of intestinal cholesterol synthesis by Ro 48-8071, an inhibitor of 2,3-oxidosqualene:lanosterol cyclase, in the BALB/c mouse

“…This has been achieved through utilization of genetically manipulated mouse models together with novel agents such as ezetimibe and also plant sterols and stanols [10–21]. These endeavors have helped make the pharmacologic control of cholesterol absorption an increasingly attractive target for the management of dyslipidemia in the general population [22]. …”

Sepiolite Clay Attenuates the Development of Hypercholesterolemia and Obesity in Mice Fed a High-Fat High-Cholesterol Diet

“…10 Statins reduce blood cholesterol level by reducing its endogenous production. 11 However, statin monotherapy is not well tolerated at high doses, 12 raising the need for coprescription with nonabsorbable cholesterol sorbents and/or with cholesterol absorption inhibitors. 10,11 In this study, we examine the effectiveness of sepiolite supplementation as a nonabsorbable cholesterol sorbent that could reduce the need for statins while also attenuating obesity.…”