Combined co-morbidities have a major impact on the pathogenesis of heart failure, which led to the supposition that myocardial dysfunction may not originate exclusively in the heart itself, but extrinsic factors that stem from these co-morbidities may perturb the heart [
115]. Here, current knowledge on the role of LXRs in the pathogenesis of several of these co-morbidities, including atherosclerosis and vascular disease, hypertension, diabetes, metabolic syndrome, and chronic kidney disease, is summarized (Table
1). Given the widespread effects of LXRs, we postulate that systemic LXR activation may play an important role in conferring myocardial protection from these disorders that collectively contribute to the pathogenesis of HFrEF and HFpEF.
Table 1
Systemic effects of liver X receptor activation in relation to co-morbidities relevant in heart failure pathogenesis
↑ Cholesterol efflux [ 102, 103] | ↑ Renin modulation [ 92, 127] | ↑ Glucose tolerance [ 18, 77] | ↓ Albumin:creatinine ratio [ 72, 99, 126] |
↓ Lesion development [ 64, 128] | ↓ AT1R expression [ 57, 76, 80] | ↑ Insulin sensitivity [ 18] | ↓ Lipid accumulation [ 72, 99] |
| | ↓ Endothelial dysfunction [ 50, 83] | |
↑ Vascular protection [ 11] [ 22] | ↓ Blood pressure [ 75, 80] | | |
| ↑ Neurological events [ 69] | | |
↑ Hypertriglyceridemia [ 113] | ↑ Psychiatric events [ 69] | | |
LXR and atherosclerosis
Atherosclerosis contributes to multi-organ dysfunction involving the kidney, brain, gut, and skeletal muscle, and is a major cause of HFrEF following myocardial infarction. LXRs have been extensively studied for their putative atheroprotective functions [
15]. The initial stages of atherosclerosis involve the formation of foam cells by the uptake of oxidized low-density lipoprotein (LDL) in macrophages in the arterial wall. Mice deficient for both LXRα and LXRβ develop increased foam cell formation, implicating a basal role in cholesterol homeostasis [
114]. LXRs limit pathogenic accumulation of cholesterol in macrophages by enhancing the rate of cholesterol efflux [
94], which is mediated through upregulation of genes involved in all aspects of the reverse cholesterol transport (RCT) pathway, including Abca1, Abcg1, and ApoE in cellular cholesterol efflux, CETP and PLTP in plasma lipid transport, Abcg5 and Abcg8 for entero-hepatic sterol absorption and excretion, and Cyp7a1 for enhanced bile acid excretion [
109]. In murine models, LXR agonist treatment significantly reduced atherosclerosis in both
Ldlr
−/− and a
poE
−/− mice [
64], whereas selective loss of macrophage LXR activity through bone marrow transplantations markedly increased lesion development in these models [
128]. Interestingly, liver-specific deletion of LXRα in mice leads to decreased RCT, cholesterol catabolism, and excretion while substantially increasing atherosclerosis, altogether underscoring their importance as whole-body cholesterol sensors [
143].
In macrophages, the metabolic functions of LXRs are coupled to anti-inflammatory responses, which further contribute to the mechanism underlying their atheroprotective effects. LXR agonist activation inhibits the induction of pro-inflammatory cytokines through a mechanism involving transrepression [
63]. In atherogenic
Ldlr
−/− mice, selectively increasing LXRα in macrophages leads to reductions in plasma inflammatory cytokines, IL6 and TNFα, and atherosclerotic lesion development [
82]. Moreover, in the absence of cholesterol efflux pathways mediated by
Abca1/g1-deficient macrophages, LXR agonism nonetheless decreased lesion area, complexity, and inflammatory cell infiltration, including plasma levels of the chemokine, MCP1 [
67]. LXRs have also been shown to target the inflammatory process in atherogenesis at a critical step through the inhibition of chemokine-induced CD4-positive lymphocyte migration [
133].
More recent evidence implicates additional atheroprotective properties of LXR agonists in the pathogenesis of atherosclerosis that extend beyond their capacity to promote peripheral cholesterol efflux and inhibit inflammation. A novel anti-atherosclerotic mechanism for LXRα through regulation of macrophage iron homeostasis has been identified. By increasing iron export, LXRα reduces iron loading which promotes formation of oxidized lipids, an inducer of cell death [
12]. Other functions for LXRs within the vasculature are emerging. Endothelial dysfunction is the underlying cause of all vascular diseases and is a critical initiator of atherosclerosis. LXRs are expressed in endothelial cells [
121], and their distribution in murine aortas reveals a greater degree of expression in the atheroprotective thoracic region than in atheroprone areas such as the aortic arch, supporting an anti-atherogenic function [
145]. In atherosclerotic vessel walls, studies indicate that LXR activation decreases vascular expression of adhesion molecules such as E-selectin, ICAM-1, and CD44 [
131], and improves arterial vasomotor function through enhanced endothelium-dependent vasorelaxation [
22].
Also of relevance are the reparative effects of LXRs in vascular injury. The progression of atherosclerosis is accelerated via denuding of the endothelium and intimal injury, which are accompanied by platelet deposition, thrombus formation, and smooth muscle cell proliferation. In rodent models of carotid artery injury, LXR ligands repaired damaged vessel walls by advancing endothelial regeneration through increased proliferation and migration of endothelial progenitor cells and enhancing their secretion of vascular endothelial growth factor (VEGF) [
140], as well as inhibiting vascular smooth muscle cell proliferation and neointima formation [
11]. Also of note is the identification of a novel role for LXRs in thrombosis and platelet function. Although platelets are anuclear, they reportedly express LXRβ and GW3965 treatment has been shown to inhibit platelet accumulation and thrombi formation [
122].
Taken together, evidence of an atheroprotective role for LXRs continues to broaden as studies reveal novel functions in cholesterol efflux, macrophage activity, and vascular protection. Preventing atherosclerotic lesion development is of paramount importance in offsetting coronary syndromes such as myocardial infarction, the major cause of systolic dysfunction leading to HFrEF. Thus, LXRs represent a promising target in the etiology underlying HFrEF and subsequent mortality.
LXR and hypertension
In HFpEF, hypertension is the most prevalent co-morbidity [
89] and precedes heart failure in 60–90 % of all cases [
81]. Besides being a risk factor for atherosclerosis and causing vascular injury, hypertension affects the cardiac muscle by invoking pathological hypertrophic growth through increased hemodynamic afterload.
The RAAS is a predominant hormonal signaling pathway in the regulation of blood pressure, fluid balance, and systemic vascular resistance. LXRs have been implicated in blood pressure control through modulation of the RAAS. Initial observations identified LXRα as a regulator of renin transcription [
92,
127]. Acute administration of LXR agonists directly increased renin mRNA levels in vivo, whereas LXR-null mice lost their capacity to upregulate renin under β-adrenergic stress [
92], suggesting a crosstalk between LXR signaling and the RAAS. In subsequent studies,
chronic LXR activation inhibited isoproterenol-induced components of the RAAS, including renin, but also angiotensin converting enzyme (ACE) and angiotensin type I receptor (AT1R) expression in kidneys and heart [
76]. Furthermore, in vivo investigation of the functional effects of LXRs on RAAS activation revealed that LXR agonism abolished angiotensin (Ang) II-induced increases in blood pressure in rats [
80]. Although improved vasoreactivity was not unequivocally linked to the level of RAAS activation, these findings suggest that LXRs decrease peripheral vascular resistance and potentially lower blood pressure. In line with this, the LXR agonist T09 was found to reduce the elevation in blood pressure due to chronic pressure–volume overload in mice, whereas this effect was absent in mice lacking LXRα [
75].
The RAAS is not only regulated by mechanisms that stimulate renin release, but is also modulated by natriuretic peptides, ANP and BNP, which are produced by the heart and antagonize the RAAS pathway. Recently, overexpressing cardiac LXRα has been shown to upregulate natriuretic peptide expression [
16] (Cannon et al., unpublished data); therefore, LXRα modulation of natriuretic peptides may represent an indirect mechanism for RAAS suppression. Overall, existing evidence suggests that LXRs play a role in antagonizing RAAS activation and may be a viable target in alleviating the hemodynamic burden imposed on the heart.
LXR and diabetes
Disturbances in energy balance leads to impaired peripheral glucose utilization and the development of insulin resistance and type II diabetes, both of which increase the risk for cardiovascular disease [
58]. Diabetes accelerates atherosclerosis, but also directly causes myocardial hypertrophy and diastolic dysfunction in the absence of hypertension or coronary artery disease [
43].
LXR agonists have been recognized as a potential pharmacological strategy for the treatment of diabetes and associated metabolic disorders [
45]. Multiple studies have established the importance of LXRs in glucose metabolism and in the adaptation to metabolic stress that triggers diabetes. In rodent models of type II diabetes and insulin resistance, LXR agonists have been shown to reduce plasma glucose [
18,
84] and improve glucose tolerance and insulin sensitivity [
18,
29,
48,
77,
84]. Mechanisms underlying the beneficial effects of LXRs on glucose homeostasis span several organ systems including the liver, adipose tissue, skeletal muscle, and pancreas. In the liver, LXR agonists suppress gluconeogenesis by downregulating Pgc1a, Pepck, and G6Pase genes, and induce glucokinase to promote hepatic glucose utilization [
18,
77,
125]. In adipose tissue and skeletal muscle, LXRs directly regulate transcription of the glucose transporter, Glut4, and enhance peripheral glucose uptake both in the absence [
33,
77] and presence of diabetes [
6,
68]. In pancreatic islet cells, an important homeostatic role for LXRβ has been elucidated as
Lxrβ
−/− mice are intolerant to glucose due to impaired glucose-stimulated insulin secretion [
44], whereas LXR ligands have been found to promote β-cell insulin secretion [
39,
44,
48].
Although LXR agonists represent promising anti-diabetic agents given their insulin-sensitizing effects, the favorable effects on glucose metabolism need to be dissociated from their lipogenic effects for these compounds to be of potential clinical use (Table
1). LXR agonists enhance hepatic and skeletal muscle lipid accumulation and increase circulating triglycerides [
30,
68], which worsens the lipogenic pathology in diabetes [
26]. Chronic LXR activation may also impair insulin secretion by contributing to lipotoxicity-induced pancreatic β-cell apoptosis [
27]. To circumvent these ramifications, alternative approaches are being initiated which include the development of partial LXR ligands or LXRβ-specific agonists since lipogenesis is mediated primarily via LXRα [
59]. Interestingly, a recent study reported that administration of the LXR agonist T09 in combination with metformin, an established oral anti-diabetic drug, ameliorated the development of hepatic steatosis induced by LXR agonism in diabetic rats [
49], suggesting that combinatorial therapies may also be viable.
Apart from metabolic dysregulation, diabetes is also characterized by low-grade inflammation that stems from macrophage infiltration in adipose tissue and secretion of pro-inflammatory cytokines [
129]. By antagonizing NFκB signaling in the nucleus, LXRs have been shown to inhibit the induction of pro-inflammatory genes encoding iNOS, COX-2, IL6, and MCP1 [
63]. To date, the impact of the anti-inflammatory functions of LXRs on diabetic pathophysiology is largely unknown. Since chronic systemic inflammation predisposes toward myocardial dysfunction and resultant HFpEF [
100], we postulate that LXRs may protect the heart, amongst other susceptible organs, from diabetes- and obesity-induced inflammation.
In summary, LXRs are implicated in the protection against diabetes through modulation of glucose metabolism, β-cell insulin secretion, and inflammatory signaling, including recent developments indicating vasoprotection from hyperglycemia-induced endothelial dysfunction [
50,
83]. Overall, LXRs mediate several pathways involved in diabetes, and as such, potentially affect the pathogenesis of HFpEF. These multiple effects are also linked to other co-morbidities contributing to heart failure development: atherosclerosis, the major cause of HFpEF, which is further aggravated by the presence of diabetes, as well as diabetes-induced kidney damage, which results in renal dysfunction, failure, and eventual HFpEF (discussed below).
The metabolic syndrome is comprised of a cluster of metabolic abnormalities that include disturbances in glucose homeostasis, insulin resistance, obesity, dyslipidemia, and elevated blood pressure. These conditions increase the risk of developing cardiovascular disease and diabetes. Maintaining glucose homeostasis and improving insulin sensitivity are important effects of LXRs that potentially influence the development of insulin resistance and diabetes. However, the role of LXRs in modulating the molecular pathogenesis of the metabolic syndrome is less clear.
LXRs are critically involved in cholesterol homeostasis and lipid metabolism. In
Lxrα
−/− and
Lxrα/β
−/− mice, serum LDL is increased and HDL is decreased, but not in
Lxrβ
−/− mice, whereas serum and VLDL and LDL triglycerides are reduced in double-mutants [
114]. Further, LXR agonism treatment lowers total and unesterified cholesterol levels in atherogenic
Ldlr
−/− mice [
64]. In addition to promoting RCT [
94], LXRs have also been shown to limit LDL receptor-dependent cholesterol uptake by transcriptionally inducing Idol, an E3 ubiquitin ligase that triggers ubiquitination of the LDL receptor, targeting it for degradation [
141].
Apart from enhancing cholesterol catabolism and transport, LXRs are centrally involved in promoting hepatic lipogenesis. LXRs induce lipid synthesis by directly regulating the expression of Srebp1c and downstream target genes, Acc, Fas, and Scd1 [
108]. Furthermore, functional LXREs have been identified in the promoter region of ChREBP, a glucose-activated transcription factor that converts excess carbohydrates into lipids [
20]. LXRs are also implicated in regulating lipolysis within adipose tissue [
124]. In rodents, LXR agonism has been shown to reduce adipocyte size [
29], as well as increase serum levels of glycerol and nonesterified free fatty acids, indicative of increased triglyceride hydrolysis [
111]. Altogether, dual effects of LXRs on hepatic lipogenesis and adipocyte lipolysis promote hyperlipidemia and insulin resistance, which are undesirable phenomena in the development of the metabolic syndrome.
The effect of LXRs on obesity has also been examined. LXR null mice are resistant to diet-induced obesity and exhibit significant reductions in adipocyte size [
65,
74]. In an alternative model of genetic obesity, LXRα/β-deficient
ob/ob mice remain obese and have increased adipose lipid storage, but display reduced hepatic lipid accumulation and improved insulin sensitivity compared to
ob/ob mice [
7]. Despite being more insulin sensitive, LXRα/β-deficient
ob/ob mice are, however, glucose intolerant and have impaired pancreatic function. These data suggest that, although LXRs may not protect against obesity, their expression nevertheless influences lipid accumulation, insulin sensitivity, and glucose homeostasis in the setting of obesity [
7]. Other studies have shown that LXRs may affect obesity through modulating pathways involved in nutrient status and energy expenditure. LXR agonism downregulated leptin expression in white adipose tissue in mice as well as decreased UCP1 expression, leading to increased energy intake and decreased energy expenditure, respectively [
125].
Alternatively, LXRs may protect against obesity through anti-inflammatory functions that ameliorate the development of insulin resistance. LXR agonism has been shown to inhibit TNFα-stimulated release of inflammatory cytokines in fat cells, while re-establishing insulin sensitivity [
41]. Thus overall, there is sufficient evidence to suggest that LXRs modulate key components of the metabolic syndrome.
LXR and chronic kidney disease
Nephropathy is a microvascular complication of diabetes mellitus and uncontrolled hypertension, leading to chronic kidney disease [
112]. These, and other causes of chronic kidney disease, are major contributors to cardiac damage and are associated with an increased risk for cardiovascular disease [
13,
117].
LXRs have been implicated as a renoprotective target, preserving intrinsic renal structure and function both basally and in diabetic nephropathy. A homeostatic role for LXRs in kidney function has been postulated.
Lxrβ
−/− mice exhibit polyuria and polydipsia, features of diabetes insipidus [
42], and mice deficient for both LXRs display a renal phenotype analogous to diabetic nephropathy with elevations in albumin:creatinine ratio and glomerular lipid accumulation [
99]. When challenged with diabetes, these mice demonstrated accelerated mesangial matrix expansion, increased glomerular lipid, and upregulation of inflammatory and oxidative stress markers [
99].
In the kidney, expression levels of both LXRs are significantly decreased in animal models of type I diabetes [
105] and in patients with diabetic nephropathy [
87]. Studies conducted in several diabetic rodent models demonstrated that LXR activation with T09 and GW3965, as well as a new generation agonist, N,N-dimethyl-3β-hydroxycholenamide (DMHCA), prevented renal damage and dysfunction by reducing urinary albumin excretion and inhibiting macrophage infiltration, inflammation, and lipid accumulation [
72,
99,
126]. Besides local renal effects, macrophage-derived LXR signaling is also pertinent in renal pathophysiology as transgenic LXRα overexpression in macrophages protected from hyperlipidemic-hyperglycemic nephropathy [
72]. These findings suggest that LXRs play an important role in hyperglycemic-induced kidney disease. Whether LXRs affect hypertension-associated renal impairment remains to be established.