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Interplay between Epigenetics and Hyperlipidemia may cause Insulin Resistance

Interplay between Epigenetics and Hyperlipidemia may cause Insulin Resistance. Claudia C. Ramirez Sanchez Ali Kuraishy , Ph.D. University of California San diego. A little bit of background.

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Interplay between Epigenetics and Hyperlipidemia may cause Insulin Resistance

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  1. Interplay between Epigenetics and Hyperlipidemia may cause Insulin Resistance Claudia C. Ramirez Sanchez Ali Kuraishy, Ph.D. University of California San diego

  2. A little bit of background • Epigenetics: Changes in phenotype from causes above the level of DNA, from structural changes (histones and methylation) • Hyperlipidemia: High concentration of lipids in body. • Diabetes: Condition of high glucose levels in the blood. • Type 1: Cells are Insulin dependant. Hormone Insulin is not sufficiently secreted. • Type 2: Cells are Insulin insensitive (do not respond correctly)

  3. Why is this important? • Obesity is one of the factors leading to diabetes • By 2007 diabetes affected 7.8% of the American population (American Diabetes Association). • Minorities are at a higher risk of Type 2 diabetes. • It is still unclear why Type 2 diabetes occurs.

  4. What happens is… Bacterial polysaccharide LPS + cell receptor TLR4 = inflammatory pathway  Phosphorylating epigenetic regulator BMI1.

  5. What do we address? • High concentration of free fatty acids may be signaling through a receptor called TLR4, resulting in a failure to respond to insulin. • Understanding how this signaling results in insulin insensitivity is critical to understanding Type 2 diabetes and identifying novel targets for therapy.

  6. Hypothesis • Free fatty acids may signal through TLR4 and phosphorylate the epigenetic regulator BMI1, thus modulating its activity and changing the expression levels of a wide variety of genes. Chronic phosphorylation of BMI1 may result in semi-permanent epigenetic changes which may then result in insulin insensitivity.

  7. Methods • Western Blots: To determine BMI1 phosphorylation by free fatty acids. (LPS, BSA, Palmitic Acid in macrophages and fibroblasts) • Co-immunoprecipitation: To determine what proteins are phosphoryalting BMI1.

  8. Methods • Cloning BMI1: To determine where BMI1 is being phosphroyated BMI1 insert is ligated into pGEX vector in order to clone the insert.

  9. Results WT JNK1-/- • From this Western blot, we think that there may be a difference in BMI1 phosphorylation between hepatocytes from mice fed a low fat versus a high fat diet. - LPS - LPS p-BMI1 BMI1 • BMI1 is phosphorylated after LPS treatment in a JNK1-dependent manner p-BMI1 BMI1 Mice fed with high fat diet (H1, H2, H3 show more phosphorylation than mice fed a low fat diet (L1,L2,L3) L1 L2 L3 H1 H2 H3

  10. Conclusion and Future Directions In conclusion… What’s next? • Data is still inconclusive in many regards. • There is a difference in BMI1 phosphorylation between hepatocytes from mice fed a low fat and a high fat diet. (High fat diet = More BMI1 phosphorylation) • Find clear demonstration that free fatty acids phosphorylate BMI1. • Isolate the BMI1 protein and incubate it with lysates from LPS treated cells together with radioactive p32.

  11. Acknowledgements • Dr. Ali Kuraishy for giving me the opportunity to work under his supervision. • Anne Chang (Manager), Dr. Michael Karin’s Lab, and Dr. Emil Bogennman and Mercedes Gonzalez from the STEP-UP Program. • MESA Program at Southwestern College, NSF and LIPP Family Foundation

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