Casting a shadow on liver X receptor-mediated atheroprotection: is LXRβ to blame?
Version of Record online: 27 JUL 2012
© 2012 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
Volume 272, Issue 5, pages 449–451, November 2012
How to Cite
Degirolamo, C. and Moschetta, A. (2012), Casting a shadow on liver X receptor-mediated atheroprotection: is LXRβ to blame?. Journal of Internal Medicine, 272: 449–451. doi: 10.1111/j.1365-2796.2012.02561.x
- Issue online: 22 OCT 2012
- Version of Record online: 27 JUL 2012
- Accepted manuscript online: 31 MAY 2012 12:29PM EST
Deciphering the molecular mechanisms underlying cholesterol homoeostasis is one of the most interesting and clinically relevant challenges in the field of cardiovascular research as hypercholesterolaemia is a major risk factor for atherosclerosis and for coronary heart disease (CHD) mortality. A complex network consisting of cellular components (including sterol transporters and cholesterol-metabolizing enzymes) and transcriptional sensors balances cholesterol absorption and endogenous synthesis with biliary excretion and conversion to bile acids (BAs).
Liver X receptors (LXRs) are sterol-responsive transcription factors that function as chief regulators of cholesterol homoeostasis by controlling cholesterol influx, transport and efflux . Studies in LXR-deficient mice [2, 3] and use of LXR agonists have provided compelling evidence that LXRs are critical for cholesterol homeostasis and exert atheroprotective effects including promotion of reverse cholesterol transport (RCT), elevation of high-density lipoprotein (HDL) cholesterol levels, inhibition of cholesterol absorption and repression of inflammatory signalling pathways .There are two LXR isoforms, LXRα and LXRβ, in mammals. LXRα is highly expressed in the liver, intestine, adipose tissue and macrophages, whereas LXRβ has a ubiquitous expression pattern. Use of LXR agonists in the therapeutic management of CHD has been hampered by the observation that LXR-driven atheroprotection is accompanied by hypertriglyceridaemia, which has been attributed to the LXRα isoform . The relative contributions of the LXR isoforms to the pathophysiology of metabolic disorders including atherosclerosis and type 2 diabetes remain unknown; however, the therapeutic potential of isoform-specific LXR modulation has recently received much attention [6, 7]. Thus, several groups have focused on strategies targeting LXRs in an isoform-specific or tissue-selective manner to promote RCT and increase HDL whilst avoiding induction of lipogenesis [8–11].
Although macrophages have been implicated as a critical site of action for LXR-mediated atheroprotection [12–14], LXR activation has been shown to inhibit cholesterol absorption pointing to an important role of LXRs in the intestine . To date, inhibition of cholesterol absorption has been regarded as a potential strategy in cardiovascular prevention, which is able to efficiently lower plasma LDL cholesterol levels, the major risk factor for CHD. Studies in animal models support the notion that inhibition of cholesterol absorption can offer atheroprotection , whilst in humans, conclusive evidence for the efficacy of the cholesterol absorption inhibitor, ezetimibe, with regard to atherosclerosis regression and reduction in cardiovascular mortality rate is eagerly awaited . Although LXRs control the intestinal cholesterol absorption pathway by modulating the expression of key players such as ATP-binding cassettes (ABC) G5 and A1 and Niemann-Pick C1-like 1 (NPC1L1), the relative contributions of the two LXR isoforms have not been directly evaluated in the context of cholesterol and BA metabolism.
In a study reported in this issue of the Journal of Internal Medicine, Hu et al. have investigated the biological relevance of LXRα and LXRβ isoforms in intestinal cholesterol absorption . The authors focused on the metabolic consequences of LXR isoform-selective activation using isoform-specific null animals challenged with dietary cholesterol and treated with the pan LXR agonist GW3965. They demonstrated that systemic LXRβ activation increases intestinal cholesterol absorption, whilst decreasing faecal neutral sterol excretion without affecting biliary sterol output. Increased cholesterol absorption observed upon LXRβ activation is accompanied by higher plasma total cholesterol, elevated levels of apolipoprotein (apo) B–containing lipoproteins and a higher percentage of hydrophobic BAs in the faeces. By contrast, systemic LXRα activation does not affect either intestinal cholesterol absorption or hepatic cholesterol deposition whilst increasing faecal neutral sterol excretion and biliary sterol output.
It is interesting that both LXR isoforms compensate for each other in the transcriptional regulation of ABCG5, ABCA1 and NPC1L1 proteins. Furthermore, the hepatic BA-synthesizing enzymes cholesterol 7-alpha-hydroxylase (CYP7A1) and sterol12-alpha-hydroxylase (CYP8B1) are differentially modulated upon systemic LXR isoform activation; the CYP7A1 transcript is more responsive to LXRα than to LXRβ stimulation, whereas CYP8B1 appears to be down-regulated by LXRβ but not LXRα activation (Fig. 1). Given the contribution of the hydrophobicity of the BA pool to intestinal cholesterol absorption, these changes together with the net differences in biliary cholesterol output may partly explain the isoform-mediated differences in cholesterol absorption. The findings of this interesting study reinforce the notion that LXRα and LXRβ do not perform identical functions, at least in mice, and suggest that isoform-specific strategies may lead to undesired metabolic consequences.
Several aspects of this thought-provoking work deserve consideration. First, the lipid and lipoprotein phenotype observed upon LXR isoform-specific activation should be urgently investigated with regard to the extent and development of atherosclerosis in susceptible mouse strains (i.e. LDL receptor- and apoE-deficient mice) in order to reconcile the reported findings with previous work on the atheroprotective potential of LXRβ on macrophage RCT and cholesterol overload [8–10, 14]. In line with this, a recent study supports the need of LXRα for the atheroprotection in apoE-deficient mice . Second, the possibility should be considered that the metabolic changes ascribed to LXRβ activation may be because of systemic LXR activation in an LXRα-null background, which displays a disrupted cholesterol homoeostasis that itself might blunt some of the observed effects . As LXRβ-selective agonists are not yet available, tissue-selective LXRβ activation could be employed to unravel LXRβ-specific effects, as already shown with regard to the specific activity of the LXRα isoform in the intestine . Indeed, the authors demonstrate tissue-specific effects of LXRβ on the regulation of the ABCG5 transcript, without induction of hepatic genes upon LXRβ activation (and associated with no change in biliary sterol output), and induction of intestinal gene to a similar level during LXRβ or LXRα activation. Third, LXRβ activation induces both an elevation of HDL cholesterol levels, although to a lesser extent compared with LXRα activation, and an increase in apoB-containing lipoprotein cholesterol levels (mostly the LDL fraction). In LXRα-null mice, massive accumulation of cholesteryl esters occurs in response to dietary cholesterol challenge, and this excess of cholesteryl esters is likely to be incorporated into apoB-containing lipoproteins by the enzyme acyl-CoA:cholesterol acyltransferase 2, which is not directly regulated by LXRs at the transcriptional level. Thus, the results of Hu et al. provide an impetus for further investigation into the cellular components underlying the LXRβ-mediated elevation of apoB-containing lipoprotein cholesterol levels. Finally, whilst this study is an elegant example of a multidisciplinary approach to the study of cholesterol metabolism, the measurement of whole-body cholesterol fluxes could provide further clarification. Indeed, the data presented here show the novel and intriguing notion that LXRβ activation increases intestinal cholesterol absorption which, in contrast to the findings of previous studies, is not reduced when both LXR isoforms are activated in wild-type mice. Moreover, it could be argued that a twofold increase in biliary cholesterol output may determine an underestimation of the degree of cholesterol absorption as measured by the authors using dual mass cholesterol technique.
Although further studies are needed to fully understand the contributions of isoform- and tissue-specific LXRα and LXRβ to cholesterol homoeostasis, the findings of Hu and co-workers have provided new insights into this important area of research. A deeper knowledge of LXR biological roles is vital to provide a greater understanding of the cellular and molecular mechanisms underlying whole-body cholesterol homoeostasis.
Conflict of interest statement
No conflict of interest was declared.
AM is funded by the Italian Association for Cancer Research (AIRC, IG 10416), Italian Ministry of University (FIRB IDEAS RBID08C9N7), Italian Ministry of Health (Young Researchers Grant GR-2008-1143546), EU FP7/2007-2013 under Grant Agreement No. 202272 (LipidomicNet), Cariplo (Milan), and the University of Bari (IDEA GRBA0802SJ-2008).