Synthetic LXR agonists increase LDL in CETP species

Abstract

Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7 ␣ -hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies.These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism. The liver X receptors LXR ␣ and LXR ␤ (1) are ligandactivated transcription factors of the nuclear receptor superfamily that control the expression of genes involved in cholesterol homeostasis and fatty acid metabolism (2, 3). LXR ␣ is highly expressed in liver (hence its name) but is also prevalent in adipose tissue, gut, kidney, and macrophages. LXR ␤ is more widely expressed and found in most tissues. Natural ligands for LXRs are oxidized derivatives of cholesterol, such as 24 S -and 25-epoxycholesterol and 24 S -and 22 R -hydroxycholesterol (4-6). LXRs are intracellular cholesterol sensors that upregulate key enzymes and transporters of cholesterol metabolism and transport, such as ABCA1 and ATP binding cassette protein G1 (ABCG1) (7-9), ABCG5 and ABCG8 (10, 11), apolipoprotein E (apoE) in adipocyte and macrophages (12), and cholesteryl ester transfer protein (CETP) (13). In mice but not in primates, hepatic cholesterol 7 ␣ -hydroxylase (cyp7a) is also upregulated by LXR (5,14,15). LXR also affects triacylglycerol metabolism by stimulating lipogenesis and triglyceride synthesis attributable to the upregulation of sterol-regulatory element binding protein 1c (SREBP1c) and the FAS complex (16,17). In addition, LXRs also have direct anti-inflammatory effects by downregulation of several proinflammatory genes in macrophages (18)(19)(20). Based on these data, LXR has been considered an attractive antiatherosclerosis target. Using the potent synthetic LXR agonist GW3965, our group collaborated in a study Abbreviations: ABCG1, ATP binding cassette protei...

Polyphenol-Rich Bilberry Ameliorates Total Cholesterol and LDL-Cholesterol when Implemented in the Diet of Zucker Diabetic Fatty Rats

“…In the present study, the expression of LXR-α was downregulated by the bilberry diet compared with the control diet (fold change = 0.76), consistent with the lower cholesterol levels. LXR-α promotes the hepatic production of apolipoprotein B-containing lipoprotein particles [29], and synthetic LXR agonists have been shown to increase LDL-cholesterol and apolipoprotein B in non-human primates [30]. In addition, LXR-α activation promotes cholesterol biosynthesis and lipogenesis through the regulation of lipogenic master genes like SREBP-1c and SREBP2 [31].…”

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

“…In this report, the lead compound from this series, WAY-252623 (LXR-623), a novel partial LXR agonist, is profi led more extensively in several animal models, including a nonhuman primate. This unique LXR ligand exhibits an improved therapeutic index that diverges from that described previously for other LXR ligands in species expressing CETP, including hamsters and cynomolgus monkeys ( 20,21 ). A direct comparison of LXR-mediated effects with a statin cholesterol-lowering drug and combination therapy are also illustrated in the primate model.…”

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

“…However, existing LXR agonists have the unavoidable side effect of activating fatty acid synthase and sterol response element-binding protein-1c in the liver, which leads to hypertriglyceridemia and hepatic steatosis, particularly in species such as humans that express cholesterol ester transfer protein (31). Although LXR agonists such as GW3965 can safely be used in mice, which lack cholesterol ester transfer protein, LXR agonists have not yet been evaluated in humans.…”