Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice

Smet, Muriel; Hoecke, Lien Van; Beuckelaer, Alain De; Beken, Seppe Vander; Naessens, Thomas; Vergote, Karl; Willart, Monique; Lambrecht, Bart N.; Gustafsson, Jan‐Åke; Steffensen, Knut R.; Grooten, Johan

doi:10.1002/iid3.118

Cited by 19 publications

(17 citation statements)

References 30 publications

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“…Liver X receptors are other important nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis (28). A primary function of LXRα as a cholesterol sensor is to maintain cellular cholesterol homeostasis by participating in the process of reverse cholesterol transport (29). LXRα can regulate the expression of genes involved in reverse cholesterol transport, such as ABCA1 and ABCG1, which mediate cholesterol efflux to lipid-poor apolipoproteins (30).…”

Section: Discussionmentioning

confidence: 99%

Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet

Han¹,

Zhang²,

Zhang³

et al. 2019

Food & Nutrition Research

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Background Dietary intake of cereal fiber has been reported to benefit lipid metabolism through multiple mechanisms. The present study aimed to discover the potential mechanisms by which cereal fiber could modify the intestinal cholesterol metabolism. Design Male C57BL/6 mice were fed a reference chow (RC) diet; high-fat, high-cholesterol (HFC) diet; HFC plus oat fiber diet; or HFC plus wheat bran fiber diet for 24 weeks. Serum lipids were measured by enzymatic methods. Western blot was used to determine the protein expressions involved in intestinal cholesterol metabolism. Results Our results showed that HFC-induced elevations of serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol were normalized in both groups that received cereal fiber. At the protein level, compared with the HFC diet group, the two cereal fibers, especially the oat fiber, significantly increased the protein expression of peroxisome proliferator-activated receptor alpha, liver X receptor alpha, sterol regulatory element-binding protein (SREBP) 2, low-density lipoprotein receptor, adenosine triphosphate (ATP)-binding cassette A1, and ATP-binding cassette G1, while decreasing the protein expression of Niemann-Pick C1-like protein 1, SREBP-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, which were involved in intestinal cholesterol metabolism. Conclusion Taken together, increased intake of cereal fiber improved blood cholesterol profiles and increased the intestinal cholesterol efflux and cholesterol clearance in C57BL/6 mice fed a HFC diet. Oat fiber had a stronger effect than wheat bran fiber on cholesterol metabolism by modulating the PPARα, LXRα, and SREBP signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet

Han¹,

Zhang²,

Zhang³

et al. 2019

Food & Nutrition Research

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“…In an ovalbumin model of asthma in BALB/C mice, GW3965 was reported to worsen airway hyperresponsiveness without affecting inflammation (Birrell, et al, 2008). By contrast, another group has shown that LXR-null mice from a different genetic background have reduced eosinophilic inflammation, mucus, and airway hyperresponsiveness in both the ovalbumin and house dust mite models of asthma, whereas GW3965 aggravates eosinophilia (Smet, et al, 2016).…”

Section: Lxr Agonists In Preclinical Models Of Inflammatory Diseasementioning

confidence: 98%

The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

Fessler

2018

Pharmacology & Therapeutics

119

112

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The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.

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“…Metabolites of the MA pathway, particularly the isoprenoids, have been associated with processes linked to asthma and respiratory ailments, including allergic eosinophilic inflammation [31,36,69], Rho GTPase signaling in airway smooth muscle cells and airway hyperreactivity (AHR) [48,70,71], adaptive immunity and type 2 inflammation [72,73], airway smooth muscle cell proliferation [43], and mucus production [74] (Figure 2). Since these pathogenic mechanisms occur in asthma, perturbation of the MA pathway likely affects disease pathogenesis [29,70].…”

Section: The Mevalonate Pathway Statins and Relevance To Asthmamentioning

confidence: 99%

Innovations in asthma therapy: is there a role for inhaled statins?

Zeki

Elbadawi-Sidhu

2018

Expert Review of Respiratory Medicine

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Introduction Asthma manifests as chronic airflow obstruction with persistent inflammation and airway hyperresponsiveness. The immunomodulatory and anti-inflammatory properties of the HMG-CoA reductase (HMGCR) inhibitors (a.k.a. statins), suggest a therapeutic role in chronic inflammatory lung diseases. However, despite positive laboratory investigations and promising epidemiological data, clinical trials using statins for the treatment of asthma have yielded conflicting results. Inadequate statin levels in the airway compartment could explain these findings. Areas covered HMGCR is in the mevalonate (MA) pathway and MA signaling is fundamental to lung biology and asthma. This article will discuss clinical trials of oral statins in asthma, review lab investigations relevant to the systemic versus inhaled administration of statins, address the advantages and disadvantages of inhaled statins, and answer the question: is there a role for inhaled statins in the treatment of asthma? Expert commentary If ongoing investigations show that oral administration of statins has no clear clinical benefits, then repurposing statins for delivery via inhalation is a logical next step. Inhalation of statins bypasses first-pass metabolism by the liver, and therefore, allows for delivery of significantly lower doses to the airways at greater potency. Statins could become the next major class of novel inhalers for the treatment of asthma.

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Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice

Cited by 19 publications

References 30 publications

Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet

Cereal fiber improves blood cholesterol profiles and modulates intestinal cholesterol metabolism in C57BL/6 mice fed a high-fat, high-cholesterol diet

The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

Innovations in asthma therapy: is there a role for inhaled statins?

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