Mechanisms for cholesterol homeostasis in rat jejunal mucosa: effects of cholesterol, sitosterol, and lovastatin

The effects of feeding cholesterol, sitosterol, and lovastatin on cholester ol absorption, biosynthesis, esterification, and LDL receptor function were examined in the rat jejunal mucosa. Cholesterol absorption was measured by the dual-isotope plasma ratio method; the rate-limiting enzyme of choleste rol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase , was measured as total and expressed enzyme activities tin the absence and presence of a phosphatase inhibitor, NaF, respectively); mucosal total and esterified cholesterol concentrations were determined by gas-liquid chroma tography; LDL receptor function was assayed as receptor-mediated binding of I-125-labeled LDL to mucosal membranes. Feeding 2% sitosterol or 0.04% lov astatin for 1 week significantly (P < 0.01) decreased the amounts of choles terol absorbed per day (-85% and -63%, respectively). In contrast, feeding 2% cholesterol for 1 week increased the amounts of absorbed cholesterol 27- fold, even though the percent absorption significantly decreased. With all three treatments, there was a coordinate regulation of total HMG-CoA reduct ase activity and receptor-mediated LDL binding. Cholesterol feeding downreg ulated both total jejunal HMG-CoA reductase activity (P < 0.05) and recepto r-mediated LDL binding (P < 0.01), whereas lovastatin- and sitosterol-suppl emented diets significantly upregulated both of these parameters. In the co ntrol, cholesterol-fed, and sitosterol-fed animals, about half of the total jejunal HMG-CoA reductase activity was expressed tin functional dephosphor ylated form). However, in the lovastatin-treated rats with 1-fold stimulati on of HMG-CoA reductase, only 23% of the total enzyme activity was expresse d. Changes in total HMG-CoA reductase activity and receptor-mediated LDL bi nding in all tested groups occurred with no change in total concentrations of mucosal cholesterol, and only cholesterol-fed animals had increased muco sal esterified cholesterol concentrations. Thus, in response to various flu xes of dietary or newly formed cholesterol, HMG-CoA reductase and receptor- mediated LDL binding are coordinately regulated to maintain constant cellul ar cholesterol concentrations in the jejunum.