Although presence of the metabolic syndrome seems to be associated with atherosclerotic CVD outcomes in humans,1-3
dissociation of the two has been previously reported.34
Results from this study provides evidence that the metabolic syndrome can be completely dissociated from atherosclerosis in mice. That is, in the extreme case of leanness and insulin sensitivity induced by SCD1 ASO treatment, atherosclerosis independently progressed. Results from this study support the notion7-18
that SCD1 inhibitors may be efficacious in preventing many aspects of the metabolic syndrome (diet-induced obesity, hepatic steatosis, insulin resistance, hypertriglyceridemia), but this may be at the expense of the artery wall. To help explain this unexpected finding, we propose a working model in which SCD1 inhibitors promote atherosclerosis (). Briefly, we believe that inhibition of SCD1 in the liver results in secretion of VLDL particles that are highly enriched in SFA-rich CE, giving rise to SFA-CE rich LDL particles. These SFA-CE rich LDLs deliver SFA to macrophages, which also have diminished SCD1 expression, resulting in accumulation of SFA in macrophages, enhanced TLR4-driven tyrosine phosphorylation of STAT1, and ultimately enhanced inflammatory cytokine secretion. This proinflammatory phenotype thereby promotes atherosclerosis in a hyperlipidemic setting.
Figure 6 Proposed mechanism by which SCD1 inhibition promotes atherosclerosis. Briefly, Inhibition of SCD1 in the liver results in secretion of VLDL particles that are highly enriched in saturated fatty acid (SFA)-rich cholesteryl esters (CE) and likely other (more ...)
In support of this model, a role for SCD1 in protecting against another inflammation-driven disease [dextran sulfate sodium (DSS)-induced colitis] was recently reported.35
In this report, Chen et al. elegantly demonstrated that mice lacking SCD1 had elevated DSS- and bacterial-driven inflammatory gene expression and exaggerated colitis, findings analogous to our results. This study35
, as well as ours, supports the long-standing notion that SFAs are potent proinflammatory molecules.27-30
Hence, one of the key roles of SCD1 may be to suppress inflammation by preventing excessive accumulation of SFA themselves and downstream metabolites such as stearoyl-lysophosphatidylcholine35
. Importantly, this study now joins several recent reports that have demonstrated unexpected harmful consequences of inhibiting SCD1.18,35,37
The molecular mechanism(s) by which SCD1 inhibition promotes atherosclerosis (), inflammatory colitis,35
has not been clearly elucidated. More work is needed to address these unexpected outcomes if SCD1 inhibitors are to be pursued as CVD therapeutics in humans. In addition to SCD1 inhibitors, TLR4 antagonists have been suggested as potential CVD therapeutics, yet whether TLR4 plays a role in atherosclerosis in humans has been a matter of intense debate.38-40
Indeed, more work is needed to investigate whether TLR4 is necessary for SFA-dependent induction of diseases such as atherosclerosis and the other diverse pathologies associated with SCD1 inhibition.18,35,37
, Performing SCD1 inhibition studies in TLR4 deficient mice will no doubt provide useful insight into the necessity of TLR4 in promoting both endogenous and dietary SFA-driven atherosclerosis and other inflammatory diseases.
One potential unifying mechanism driving the multiple pathologies seen under conditions of SCD1 deficiency may involve the previous documented function of SCD1 in modulating the formation of cholesterol- and SFA-rich membrane microdomains, better known as “lipid rafts”. It has been previously shown that overexpression of SCD1 in macrophages results in decreased abundance of liquid-ordered domains or lipid rafts.41
This finding correlates well with the recent report that mice lacking SCD1 in a leptin deficient background have massive accumulation of free cholesterol and SFA in pancreatic beta cells.18
Our study further supports this idea, given that SCD1 inhibition resulted in accumulation of free cholesterol and SFA in the liver (Suplemental Figure 2B and 2D
), aorta (), and isolated macrophages (data not shown). Collectively, these data suggest that SCD1 may play a crucial role in limiting accumulation of lipids (cholesterol and SFA) known to segregate into membrane liquid-ordered domains, which could potentially alter membrane-associated signal transduction.
In summary, this study demonstrates that inhibition of SCD1 protects against development of the metabolic syndrome, but may promote atherosclerosis. These results do not support the idea that obesity and insulin resistance are causatively linked to atherosclerosis, and argue against SCD1 inhibition as a safe therapeutic target for treatment of CVD.