Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

Kirchgessner, Todd G.; Sleph, Paul G.; Ostrowski, Jacek; Lupisella, John A.; Ryan, Carol S.; Liu, Xiaoqin; Fernando, Gayani; Grimm, Denise; Shipkova, Petia; Zhang, Rongan; Garcia, Ricardo Alexandrino; Zhu, Jun; He, Aiqing; Malone, Harold; Martin, Richard; Behnia, Kamelia; Wang, Zhaoqing; Barrett, Yu Chen; Garmise, Robert J.; Yuan, Long; Zhang, Jingyan; Gandhi, Mohit D.; Wastall, Philip; Li, Tong; Du, Shuyan; Salvador, Lisa; Mohan, Raju; Cantor, Glenn H.; Kick, Ellen K.; Lee, John; Frost, Robert J.

doi:10.1016/j.cmet.2016.07.016

Cited by 114 publications

(117 citation statements)

References 40 publications

(38 reference statements)

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“…Nevertheless, both the LXR agonist and rHDL studies support the concept that this method is able to assess changes in RCT. It is also noteworthy that a dosedependent increase in macrophage RCT by an LXR agonist was detectable by using this method and that it mirrored the dose-response for inhibition of atherosclerosis in mouse models (29). Data obtained from the study in healthy volunteers are consistent with those reported by Schwartz et al (11)(12)(13)(14).…”

Section: Discussionsupporting

confidence: 81%

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

Cuchel

Raper

Conlon

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org reverse cholesterol transport in vivo in humans. J. Lipid Res. 2017. 58: 752-762. Supplementary key words lipoproteins • high density lipoproteinAlthough an association between plasma concentrations of HDL cholesterol (HDL-C) levels and CVD has been found in epidemiological studies, the causal basis of this association has been recently questioned by the negative results observed in human genetics studies and clinical trials (1, 2). However, substantial interest remains in the concept that measures of HDL function may be more closely tied mechanistically to atherosclerosis (3). One of the biological functions of HDL is its ability to promote cellular cholesterol efflux and the return of that cholesterol to the liver for excretion in the feces in a process known as reverse cholesterol transport (RCT) (4). By using an in vivo assay in mice that we developed to measure the rate of RCT from macrophages to liver and feces, a large number of studies from multiple laboratories have demonstrated that the rate of in vivo macrophage RCT is a much better predictor of the impact of a genetic or pharmacologic perturbation on atherosclerosis than is the simple measure of HDL-C itself (5). Furthermore, using an ex vivo method developed to assess the cholesterol efflux capacity of HDL from a specific individual, we showed that this was strongly Abstract Reverse cholesterol transport (RCT) is thought to be an atheroprotective function of HDL, and macrophagespecific RCT in mice is inversely associated with atherosclerosis. We developed a novel method using

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Section: Discussionsupporting

confidence: 81%

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

Cuchel

Raper

Conlon

et al. 2017

Journal of Lipid Research

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“…Similar to HDCA, cholane and cholestane Lxr agonists might be useful for this purpose: while such ligands induce transcription of the master transcription factor driving de novo lipogenesis Srebf1, they simultaneously block Srebf1 proteolytic maturation by stabilizing the precursor in the endoplasmic reticulum, thereby avoiding the induction of hypertriglyceridemia and hepatic steatosis (Kaneko et al, 2003; Quinet et al, 2004; Peng et al, 2008, 2011; Kratzer et al, 2009). Non-sterol ligands lack the biophysical properties to arrest Srebf1 maturation, and their administration is marked by hepatic steatosis and hypertriglyceridemia (Schultz et al, 2000; Grefhorst et al, 2002; Bradley et al, 2007; Kirchgessner et al, 2016). Full dissection of the transcriptional program controlled by intestinal Lxrα, as well as dissection the reasons for the sexually dimorphic traits seen in our study, will provide a thorough mechanistic basis for developing new therapies that leverage the capacity of the intestine to store (and safely oxidize) absorbed fatty acids, while promoting net cholesterol elimination.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, Lxrα activation with synthetic non-sterol ligands up-regulates hepatic lipogenesis and Very Low Density Lipoprotein (VLDL) particle secretion (Repa et al, 2000; Schultz et al, 2000; Grefhorst et al, 2002; Bradley et al, 2007). This property has impeded Lxr-based drug development (Kirchgessner et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

2017

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Post-prandial hyperlipidemia has emerged as a cardiovascular risk factor with limited therapeutic options. The Liver X receptors (Lxrs) are nuclear hormone receptors that regulate cholesterol elimination. Knowledge of their role in regulating the absorption and handling of dietary fats is incomplete. The purpose of this study was to determine the role of intestinal Lxrα in post-prandial intestinal lipid transport. Using Lxrα knockout (nr1h3−/−) and intestine-limited Lxrα over-expressing [Tg(fabp2a:EGFP-nr1h3)] zebrafish strains, we measured post-prandial lipid excursion with live imaging in larvae and physiological methods in adults. We also conducted a long-term high-cholesterol dietary challenge in adults to examine the chronic effect of modulating nr1h3 gene dose on the development of hypercholesterolemia and hepatic lipid accumulation. Over-expression of Lxrα in the intestine delays the transport of ingested lipids in larvae, while deletion of Lxrα increases the rate of lipid transport. Pre-treating wildtype larvae with the liver-sparing Lxr agonist hyodeoxycholic acid also delayed the rate of intestinal lipid transport in larvae. In adult males, deletion of Lxrα accelerates intestinal transport of ingested lipids. Adult females showed higher plasma Lipoprotein lipase (Lpl) activity compared to males, and lower post-gavage blood triacylglycerol (TAG) excursion. Despite the sexually dimorphic effect on acute intestinal lipid handling, Tg(fabp2a:EGFP-nr1h3) adults of both sexes are protected from high cholesterol diet (HCD)-induced hepatic lipid accumulation, while nr1h3−/− mutants are sensitive to the effects of HCD challenge. These data indicate that intestinal Lxr activity dampens the pace of intestinal lipid transport cell-autonomously. Selective activation of intestinal Lxrα holds therapeutic promise.

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“…For example, although LXR (liver X receptor) agonists being developed as an atherosclerosis treatment did not raise LDL cholesterol levels in mice, they were found to substantially increase LDL cholesterol concentrations by inducing IDOL (which promotes degradation of the LDLR) in monkeys and humans, which precluded further clinical development. 54 Therefore, although native mice have marked differences in lipoprotein metabolism compared with humans, genetically manipulated mice have been invaluable to our understanding of molecular mechanisms and the underlying pathways involved in atherosclerosis.…”

Section: Micementioning

confidence: 99%

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

Daugherty¹,

Tall²,

Daemen³

et al. 2017

Circulation Research

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Abstract-Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions. (Circ Res. 2017;121:e53-e79.

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Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

Cited by 114 publications

References 40 publications

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

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