Pathogenesis of Dyslipidemia and Atherosclerosis in the Diabetic State

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The leading cause of death in diabetic patients is cardiovascular disease (CVD). Our long-term goal is to identify new therapeutic targets for the prevention of CVD in diabetic patients. In the first grant cycle, we identified the enzyme flavin-containing monooxygenase 3 (FMO3) as a potential mediator of diabetes-associated cardiovascular disease via a non-biased transcriptomics approach. In the second grant cycle, we found that FMO3 exerted many of its effects via the key metabolite, trimethylamine N-oxide (TMAO); we further found the endoplasmic reticulum stress kinase, PERK, to be a receptor for TMAO. Multiple clinical studies have now shown that TMAO is increased with insulin resistance, as well as atherosclerosis, confirming that this pathway is dysregulated in humans, and suggesting that inhibition of the FMO3/TMAO pathway may have beneficial effects. TMAO is synthesized from the metabolite trimethylamine (TMA), which is in turn produced by the gut microbes. Therefore, an attractive strategy would be to inhibit the production of TMA by the gut microbes. In our unpublished, preliminary data, we screened a drug repurposing library. The advantage of using repurposed drugs is that they are already known to be safe in humans, reducing the time and expense needed to bring them into the clinic. We identified a compound that inhibits the microbial enzyme that generates TMA and can lower TMAO levels in mice. The goals of the current cycle are to fill the key remaining gaps in our mechanistic understanding of the TMAO pathway, and to test the therapeutic potential of lowering TMAO. We hypothesize that TMAO, which is increased with diabetes, induces PERK to promote dyslipidemia, inflammation and diabetes-associated atherosclerosis. Our aims are to elucidate the mechanisms by which PERK promotes metabolic dysfunction; to determine the extent to which hepatic deletion of PERK can prevent TMAO-induced dyslipidemia, inflammation and atherosclerosis; and to test whether the novel compound identified in our drug repurposing screen can prevent diabetes-induced atherosclerosis in mice. We expect that these studies will lead to a novel, orthogonal approach to reducing CVD risk in patients with diabetes.