Despite an antiatherogenic lipid and metabolic profile, absence of SCD1 promotes inflammation and atherosclerosis in a mouse model of FH on a western diet. Absence of SCD1 also increases plasma IL-6, IL-1β, IL-12p70 and sICAM-1 levels and has a proinflammatory effect on the components of HDL particles, increasing SAA and apoJ/clusterin and reducing apoA-I, apoA-II, and PON1. Specific deficiency of SCD1 in bone-marrow derived cells does not influence atherosclerotic lesion size.
We have recently shown that SCD1-deficient mice have relatively reduced plasma triglycerides and are protected from obesity and insulin resistance (7
), phenotypic components of the metabolic syndrome that have been linked to increased susceptibility to atherosclerosis (25
). These surprising data suggested that SCD1-deficient mice must have some proatherogenic stimulus that overcomes the antiatherogenic metabolic characteristics expected to reduce lipid accumulation in the aorta. Chronic inflammation has been reported in the skin of chow-fed SCD1-deficient mice, indicated by increased mRNA encoding ICAM-1 (15
) and increased infiltration of macrophages and mast cells but only rare lymphocytes or neutrophils in the dermis (14
). In addition, subcutanous cyclosporin A can inhibit ICAM-1 expression and reduce mast cell numbers in the skin, restoring the wild-type skin phenotype (15
). Histopathological studies in these mice have demonstrated that the chronic inflammatory reaction is a foreign body response, with extreme sebaceous gland hypoplasia in SCD1-deficient animals resulting in hair fiber perforation of the follicle base and a foreign body response to fragments of hair fiber in the dermis (10
Inflammation is recognized to play a major role in all stages of atherogenesis (27
), and plasma markers of systemic inflammation are predictive for cardiovascular events in humans (28
). Indeed, standard preventive drug therapies such as aspirin and statins are known to have antiinflammatory properties and have been shown to be most beneficial in individuals with elevated inflammatory markers at baseline, even in those with relatively low serum cholesterol levels (30
In the LDLR-deficient mouse model, used by several groups to study the link between chronic inflammation and atherosclerosis (31
), plasma markers of systemic inflammation increase in response to dietary cholesterol, and these markers are associated with increased lesion area independent of plasma lipoprotein levels (33
). Our observations of increased plasma IL-6, a marker of systemic inflammation that is associated with atherosclerosis (28
), sICAM-1, an adhesion molecule that is elevated in serum of patients with inflammatory skin disorders (16
), and IL-1β and IL-12p70, pro-inflammatory cytokines known to be elevated in psoriatric lesional skin (18
), suggest that chronic inflammation of the skin may be contributing to the proatherogenic profile of SCD-1 deficient mice. During an inflammatory response, HDL particles are known to become depleted in apoA-I, apoA-II, and PON1 and enriched in SAA, a liver-derived protein increased by western diets and correlated with lesion area in LDLR-deficient mice (21
). Our results show that absence of SCD1 has a proatherogenic effect on HDL composition.
Atherosclerotic lesion size and macrophage cholesterol efflux are not altered in LDLR-deficient mice transplanted with bone marrow from SCD1-deficient mice. These observations, in addition to the lack of altered LPS-induced inflammatory response in SCD1-deficient peritoneal macrophages, suggest that macrophage SCD1 does not play a significant role in atherogenesis in this model. However, it should be noted that these results are from early lesions only and a longer term study is needed of SCD1 in lesion macrophages.
The SCD1-deficient mouse model affords a unique opportunity to compare and contrast directly the effects of an antiatherogenic metabolic profile with proinflammatory pathways. In this instance, proinflammatory pathways overcome the favourable metabolic profile. However, significant unanswered questions remain regarding possible atherogenic effects of circulating lipoproteins or tissue lipids with increased saturated fatty acids (SFA) or decreased monounsaturated fatty acids (MUFA), as shown in SCD1-deficient mice (2
The relevance of these findings to the development of SCD inhibitors for treatment of the metabolic syndrome in humans is unclear. Observational studies in humans have shown an association between increased indices of SCD activity and components of the metabolic syndrome (35
), inflammatory markers (38
), and potentially coronary heart disease (39
), suggesting that the atherogenic inflammation observed in this mouse model of SCD1 deficiency may not extend to humans with reduced SCD1 activity. The findings in this study represent the effects of long-term complete SCD1 deficiency in all tissues in mice. Antisense oligonucleotides (ASOs) may also be expected to result in near complete deficiency of SCD1 expression in some extra-hepatic tissues (40
), which could lead to atherogenic inflammation in rodent models similar to that observed here. By contrast, pharmaceutical compounds are generally not used at levels that would cause complete inhibition of the target enzyme through a 24-hour cycle, and would not be distributed throughout all tissues in the body.
While this manuscript was in review, two different studies reported on the relationship between atherosclerosis and SCD1 deficiency mediated by ASOs. Both groups treated mice with identical SCD1-targeted ASOs, but the experiments yielded different results: increased atherosclerosis in the Ldlr−/− Apob100/100
) and reduced atherosclerosis in the chronic intermittent hypoxia (CIH) model (42
). One clue to the discrepancy could be model-specific effects on HDL-cholesterol levels, as SCD1 deficiency is accompanied by a ~50% reduction of HDL-cholesterol levels in the dyslipidemic Ldlr−/− Apob100/100
), a change in HDL expected to be associated with increased atherosclerosis (43
). However, ASO-mediated SCD1 deficiency in the CIH model is accompanied by an atheroprotective ~20% increase in HDL-cholesterol levels (42
). Our results indicate that in the absence of changes in HDL-cholesterol levels, complete and chronic SCD1 deficiency is likely to exacerbate atherosclerosis.
These studies now provide strong support for the role of chronic inflammation in promoting atherosclerosis, even in the presence of antiatherogenic biochemical and metabolic characteristics.