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2017 Cardiovascular Research Day Abstract Book

63 Gut Microbial

63 Gut Microbial Trimethylamine (TMA) Lyase Activity Coordinates Circadian Rhythms in Host Hepatic Lipid and Bile Acid Metabolism Christy Gliniak, PhD 1 • Rebecca Schugar, PhD 1 • Robert Helsley, PhD 1 • Anthony Gromovsky 1 • Chase Neumann 1 • Zeneng Wang, PhD 1 • Stanley Hazen, MD, PhD 2 • J. Mark Brown, PhD 2 1Department of Cellular and Molecular Medicine, Cleveland Clinic • 2 Department of Cellular and Molecular Medicine, Center for Microbiome & Human Health, Cleveland Clinic Faculty From cyanobacteria to humans, circadian rhythms evolved to allow an organism to adapt and anticipate environmental cues, particularly events that regulate energy metabolism. Misalignment of circadian rhythms are associated with increased incidence of obesity, diabetes, cardiovascular disease, cancer, and other inflammatory disorders. Intestinal microbial composition and structure displays circadian rhythmicity, and the gut microbiome itself can regulate host endogenous circadian rhythms. However, it is not well understood how gut microbes regulate host metabolism and circadian rhythms. Gut microbes contribute to the production of the circulating metabolite trimethlyamine-N-oxide (TMAO), which is associated with cardiovascular disease in humans, and has been shown to enhance atherosclerosis and thrombosis potential in mice. Microbes produce trimethlyamine (TMA) from dietary choline or carnitine, which is later converted by the host to TMAO, primarily by host liver flavin monooxygenase 3 (FMO3). Previous studies have shown that pharmacologic inhibition of microbial TMA lyase activity or inhibition of FMO3 results in decreased atherosclerosis in mice, and the expression of the TMAO producing enzyme FMO3 exhibits circadian rhythmic patterns in the liver. Here we hypothesized that the co-metabolites TMA and TMAO may serve as gut microbe-derived signals that entrain host metabolic circadian rhythms, thereby impacting cardiometabolic disease. To test this we treated C57BL/6 mice with a highly potent and selective second-generation TMA lyase inhibitor CC08, and examined effects on circadian rhythms in host metabolism. As expected, mice treated with CC08 displayed reduced plasma TMA/TMAO levels across an entire 24-hour period. Unexpectedly, TMA lyase inhibition resulted in increased expression of the key nuclear receptors that regulate the circadian clock including Bmal1 (Arntl1) and Rev-erbα (Nr1d1) during the light cycle in the liver. The well known circadian cycling of transcription factors orchestrating hepatic fatty acid metabolism such as Srebp1c and Pparα were markedly altered in CC08-treated mice. TMA lyase inhibition resulted in elevated hepatic expression of Srebp1c during the light cycle, yet suppressed hepatic Pparα expression during the dark cycle. Furthermore, the expression of the bile acid-sensing nuclear receptor Fxr was lower in TMA lyase-inhibited animals during the dark cycle, which is associated with alterations in hepatic Fxr target gene expression and circulating bile acid levels. Collectively, these data suggest that pharmacologic inhibition of gut microbial TMA lyase activity can alter host transcriptional programs that dictate hepatic circadian rhythms in lipid and bile acid metabolism. These data provide the first clues into mechanisms by which TMA lyase inhibitors may protect mice against cardiometabolic disease. 79

64 Thrombospondin 1 (TSP1) Deficiency Protects Against Diet-Induced Fatty Liver Disease Courtney Turpin, MS 1 • Heather Norman-Burgdolf, PhD 2 • Ling Yao, MS 1 • Yanzhang Li, PhD 3 • Shuxia Wang, MD, PhD 1 1Department of Pharmacology and Nutritional Sciences, University of Kentucky • 2 Department of Dietetics and Human Nutrition, University of Kentucky • 3 Department of Internal Medicine, University of Kentucky Graduate Student Background: Non-alcoholic fatty liver disease (NAFLD) is a widespread disease, affecting around 20-30% of American adults with prevalence on the rise in many age groups. Obesity is thought to play a contributing role in the occurrence of this disease. NAFLD progression includes an initial state lipid accumulation, which is worsened by additional stresses. Thrombospondin 1 (TSP1) is a secreted matricellular protein that has been implicated in playing a role in causing obesityassociated inflammation, lipid accumulation, and fibrosis in various tissues, but TSP1 expression in the liver and its possible role in pathogenesis are not known. Methods: Eight-week-old control and TSP1 deficient mice were fed at either a low-fat (10% kcal from fat) or high-fat (60%kcal from fat) for 16 weeks. Liver histology, gene expression, and immunohistochemistry were performed to observe the effect of TSP1 deficiency on the liver physiology. Results: TSP1 expression was found to be significantly increased in control high-fat diet fed mice liver tissue. Liver histology showed less lipid accumulation in the TSP1 deficient mice fed a high-fat diet, which was further confirmed by reduced triglyceride levels. Although there was no significant change fatty acid uptake in the whole liver, there was a significant decrease in CD36 expression in the hepatocytes of the deficient mice, which also had reduced fatty acid uptake. There was also a significant decrease in de novo lipogenesis genes PPARγ and SREBP1c, but with normal feeding, there was no significant change in triglyceride production or secretion. In addition to the changes in lipid content, there was a reduction in inflammatory markers and the fibrosis marker Collagen1α1, but there were no observed changes in fibrosis histology staining. Discussion and implications: The findings of this study suggest that TSP1 expression could play a role in the development of the hallmark signs of NAFLD. Further studies using a NAFLD animal model and cell culture could help elucidate the mechanism of its involvement. In summary, the data suggests that TSP1 has involvement in lipid accumulation and the resulting inflammation and fibrosis that are seen in progressed disease states of NAFLD. 80

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