Pharmacological interference with intestinal bile acid transport reduces plasma cholesterol in LDL receptor/apoE deficiency

Abstract

Reduction of plasma cholesterol by statins is fundamental to prevent coronary heart disease. Such therapy is often sub-optimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the enzyme Cyp7a1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of PR835, a drug belonging to a new class of lipid-lowering agents that inhibit the Slc10a2 protein, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. Cyp7a1 enzyme activity and mRNA were induced several-fold, and hepatic HMG CoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed to induction of other known hepatic lipoprotein receptors and indicate the presence of new points of targeting in lipid-lowering therapy.

Pitavastatin, a Potent Hydroxymethylglutaryl Coenzyme a Reductase Inhibitor, Increases Cholesterol 7 .ALPHA.-Hydroxylase Gene Expression in HepG2 Cells

“…cholesterol-lowering effects. Our finding supports that of Aoki et al who reported that pitavastatin slightly increases CYP7A1 mRNA levels in guinea pigs 35 and is in agreement with that of Galman et al, 22 who reported that atorvastatin enhances the effect of IBAT inhibition on CYP7A1 mRNA levels in mice lacking both LDL-R and apo E. However, our finding does not agree with those of other authors who have reported no significant effects of lovastatin, 54 pravastatin, 34 simvastatin 35,36 or atorvastatin 30,35 on CYP7A1.…”

“…[27][28][29][30][31][32] Lovastatin had an inhibitory effect on CYP7A1 activity in rat liver; 31,33 pravastatin had no significant effect on CYP7A1 activity in human subjects; 34 simvastatin decreased CYP7A1 mRNA levels in guinea pigs, 35 but did not affect 7 -hydroxylation rates in human subjects; 36 atorvastatin decreased CYP7A1 mRNA levels in guinea pigs, 35 showed no significant effects on plasma 7 -hydroxy-4-cholesten-3-one, a validated marker of bile acid synthesis, in FH heterozygotes 30 and enhanced the effects of IBAT inhibition by PR835 on CYP7A1 mRNA and LDL-C levels in mice lacking both LDL-R and apo E. 22 However, the superstatin, pitavastatin, has been shown to slightly increase the level of CYP7A1 mRNA in guinea pigs, 35 but there is still no information available regarding its effects on CYP7A1 in humans.…”

“…17 Conversion of cholesterol to bile acids plays an important role in determining whole-body cholesterol homeostasis, 18,19 and cholesterol 7 -hydroxylase (CYP7A1) is the initial and rate-limiting enzyme in the main bile acid biosynthetic (classic or neutral) pathway. 18,20 The importance of CYP7A1 in cholesterol homeostasis is highlighted by three findings: (1) increasing hepatic CYP7A1 by bile acid depletion substantially reduces plasma cholesterol concentrations in Watanabe heritable hyperlipidemic (WHHL) rabbits, 21 in which LDL-R does not function, (2) inhibition of apical sodium codependent transporter (SLC10A2; also known as ASBT or ileal bile acid transporter, IBAT) by PR835 increases enzymatic activity and mRNA levels of CYP7A1 and drastically reduces plasma very-low-density lipoprotein (VLDL) and LDL-C in mice lacking both LDL-R and apolipoprotein (apo) E, 22 and (3) overexpression of hepatic CYP7A1 in mice lacking the LDL-R gene markedly decreases plasma concentrations of VLDL cholesterol (VLDL-C) and LDL-C. 23 The reduction in the concentration of LDL in the absence of the LDL-R gene or function by increasing CYP7A1 was caused, in large part, by intrahepatic diversion of cholesterol destined for circulating (VLDL and LDL) lipoproteins in plasma to bile acid synthesis and, therefore, to a decrease in the rate of LDL-C transfer into the plasma space. 23 Pitavastatin has been shown to decrease apo B-100 secretion from HepG2 cells through increased intracellular degradation of newly synthesized protein 24 and to strongly reduce VLDL secretion in WHHL rabbits 25 and guinea pigs.…”

Hypolipidemic Effect of Young Persimmon Fruit in C57BL/6.KOR-ApoEshlMice

“…[24][25][26] In this study, we found significant increases in fecal bile acid and hepatic SREBP-2 gene expression under YP treatment, but hepatic LDL-R gene expression did not change. To identify changes in expression at the protein level, we performed Western blot analysis for LDL-R (Fig.…”

“…Bile acid-binding resins have been reported to de-repress CYP7A1 activity and to induce hepatic LDL-R expression, resulting in stimulation of plasma LDL clearance, followed by plasma LDL reduction. 26) A slight increase in hepatic CYP7A1 gene expression was observed under YP treatment, but neither mRNA nor protein levels of hepatic LDL-R changed in the SHL-YP group, indicating that the hypolipidemic effect due to YP in C57BL/ 6.KOR-ApoE shl mice did not depend on the capacity for hepatic LDL-R. The increase in fecal bile acid excretion and the large decrease in plasma VLDL cholesterol under YP treatment suggest that acceleration of fecal bile acid excretion is a major mechanism of the hypolipidemic effect induced by YP in C57BL/ 6.KOR-ApoE shl mice.…”