Beneficial effects of β-sitosterol on type 1 cholecystokinin receptor dysfunction induced by elevated membrane cholesterol

Abstract

Background & Aims The type 1 cholecystokinin receptor (CCK1R) mediates the actions of CCK to support nutritional homeostasis, including post-cibal satiety. However, elevated levels of membrane cholesterol, such as have been observed in metabolic syndrome, interfere with CCK stimulus-activity coupling at the CCK1R, thereby disrupting this important servomechanism. We hypothesize that reversal of the negative impact of cholesterol on this receptor could be useful in the management of obesity. Methods We have studied the effects of β-sitosterol, a phytosterol structurally related to cholesterol, on CCK receptor function. This included CCK binding and biological activity at wild type CCK1R and CCK2R, as well as at CCK1R in a high cholesterol environment, and at a CCK1R mutant, Y140A, which mimics the behavior of wild type receptor in high cholesterol. Results β-sitosterol (100 μM and 10 μM) significantly improved the defective signaling of the CCK1R present in high cholesterol (p<0.05), without affecting CCK binding affinity. This effect was absent at the CCK1R present in a normal cholesterol environment, as well as at the structurally-related CCK2R. Furthermore, the cholesterol-insensitive Y140A mutant of CCK1R was resistant to the effects of β-sitosterol. Conclusion These data suggest that β-sitosterol affects CCK1R function in high cholesterol by competing with cholesterol at a receptor cholesterol-binding site and may shift its conformation toward normal. This phytosterol extends our understanding of the structure-activity relationships for developing a drug that can target the external surface of CCK1R. Since the concentrations of β-sitosterol shown to be effective in this study are similar to serum levels of this compound achievable during oral administration, it may be worthwhile to study possible beneficial effects of β-sitosterol in metabolic syndrome.

Extraction of Brazil nut kernel oil using green solvents: Effects of the process variables in the oil yield and composition

“…β‐Sitosterol is well recognized for its therapeutic efficacy as a cholesterol‐lowering agent (total plasma cholesterol and low‐density lipoprotein) (Alphonse, Ramprasath, & Jones, ; Desai, Dong, & Miller, ) and exhibits anticancerous (Sharmila & Sindhu, ) and anti‐inflammatory activities and protection against cardiovascular diseases (Desai et al, ; Shahzada et al, ), thus being an attractive source for the development of a variety of food enriched with this sterol. In the analysis of the β‐sitosterol content as a function of each of the two independent process variables studied, similar behaviors of β‐sitosterol amount was observed for the temperature and static time (Figure a,b).…”

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

“…Furthermore, whilst potent receptor agonists have been developed, these have not reached clinical practice due to limited efficacy and side effects. However, it is now clear that CCK1R activation stimulates multiple interacting signaling cascades and hopefully biased agonists targeting the satiety effects alone will overcome previous problems 20 . An alternative approach is to use positive allosteric modulators without intrinsic agonist activity to enhance the satiety effect of nutrient-stimulated endogenous CCK 20 .…”

“…However, it is now clear that CCK1R activation stimulates multiple interacting signaling cascades and hopefully biased agonists targeting the satiety effects alone will overcome previous problems 20 . An alternative approach is to use positive allosteric modulators without intrinsic agonist activity to enhance the satiety effect of nutrient-stimulated endogenous CCK 20 . Furthermore, given that CCK has been shown to interact synergistically with leptin, amylin and glucagon, combination therapies based upon these synergies are likely to be more effective than a single-agent approach.…”

Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

“…If this mechanism is utilized therapeutically, there would be advantage for an agent that more efficiently reaches the systemic circulation. β-sitosterol, a plant sterol, was recently shown to act much like ursodeoxycholic acid to correct CCK1R dysfunction when in a high cholesterol membrane environment [59]. …”