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Pharmacological interference with intestinal bile acid transport reduces plasma cholesterol in LDL receptor/apoE
Cecilia Gälman1, Ann-Margret Ostlund-Lindqvist, Anna Björquist
1Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden
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.
Insights
A new drug, PR835, effectively lowers plasma cholesterol by inhibiting bile acid uptake. Combining PR835 with statins offers a potent strategy for managing hypercholesterolemia.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Medicine
Background:
- Statins are crucial for preventing coronary heart disease by lowering plasma cholesterol.
- Therapeutic limitations exist, especially in familial hypercholesterolemia, necessitating novel lipid-lowering strategies.
- Bile acid (BA) metabolism significantly impacts cholesterol levels, with Cyp7a1 regulating its synthesis.
Purpose of the Study:
- To investigate the efficacy of PR835, a novel inhibitor of the intestinal bile acid transporter Slc10a2.
- To evaluate PR835 as a potential therapeutic agent for hypercholesterolemia, alone and in combination with statins.
Main Methods:
- PR835 treatment in mice lacking LDL receptors (LDLR) and apolipoprotein E (apoE).
- Assessment of plasma lipid profiles, including total cholesterol, LDL cholesterol, and triglycerides.
- Measurement of Cyp7a1 enzyme activity and mRNA levels, alongside hepatic HMG CoA reductase mRNA.
Main Results:
- PR835 monotherapy reduced plasma cholesterol by 40% in treated mice.
- Combined PR835 and statin therapy achieved significant reductions: 64% in total cholesterol and 70% in LDL cholesterol.
- PR835 induced bile acid synthesis and hepatic HMG CoA reductase, without affecting HDL cholesterol or triglycerides.
Conclusions:
- PR835 represents a novel class of lipid-lowering agents targeting intestinal bile acid absorption.
- Combination therapy with statins demonstrates enhanced efficacy in reducing plasma cholesterol.
- Inhibition of Slc10a2 offers a promising new therapeutic target for managing dyslipidemia and cardiovascular disease.