Abstract
Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.
Highlights
Hypercholesterolemia, especially high level of low-density lipoprotein (LDL) cholesterol, is one of the major risk factors for atherosclerotic cardiovascular disease, the leading global cause of mortality
We show that treatment with rifampicin, a human pregnane X receptor (PXR) ligand, raises serum intermediate-density lipoprotein (IDL) and LDL of all sizes and serum total, esterified and free cholesterol
Rifampicin increases the lathosterol to cholesterol ratio suggesting upregulation of cholesterol synthesis
Summary
Hypercholesterolemia, especially high level of low-density lipoprotein (LDL) cholesterol, is one of the major risk factors for atherosclerotic cardiovascular disease, the leading global cause of mortality PXR ligands increase hepatic cholesterol synthesis, plasma PCSK9 level and promote proteolytic activation of SREBP2. The mechanisms of PXR action remain controversial and both increased intestinal absorption and increased hepatic synthesis through activation of squalene epoxidase have recently been suggested to mediate PXR-induced hypercholesterolemia in mice (Gwag et al, 2019; Meng et al, 2019). To address the question if PXR activation affects human cholesterol homeostasis, we analysed serum metabolomics in controlled clinical studies investigating the cardiometabolic effects of rifampicin, the prototypic human PXR ligand, and showed metabolic signature indicating increased serum cholesterol and enhanced synthesis of cholesterol. We utilized high-fat diet challenged mice as a model to reveal the mechanism mediating PXR-induced alterations in cholesterol homeostasis and showed that PXR activation induces the cholesterol synthesis pathway, increases plasma PCSK9 and promotes sterol regulatory element-binding protein 2 (SREBP2) proteolytic activation
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