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Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids

Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids. Saraswathi Viswanathan , Ph.D. Assistant Professor Department of Internal Medicine/DEM University of Nebraska Medical Center-Omaha. Metabolic Syndrome and CVD . Abdominal obesity Atherogenic dyslipidemia

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Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids

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  1. Role of PXR Signaling in Mediating the Cardioprotective Effects of -3 Fatty Acids SaraswathiViswanathan, Ph.D.Assistant ProfessorDepartment of Internal Medicine/DEMUniversity of Nebraska Medical Center-Omaha

  2. Metabolic Syndrome and CVD • Abdominal obesity • Atherogenicdyslipidemia • Insulin resistance • Elevated blood pressure • Pro-inflammatory state

  3. Fish Oil and -3 PUFAs Fish Oil and -3 Fatty Acids EPA-Eicosapentaenoic acid DHA-Docosahexaenoic acid

  4. Clinical Evidence for the Beneficial Effects of Fish Oil • 30 g of fish per week reduced caronary artery disease (Kromhout DBE, 1985). • EPA&DHA reduced plasma TG and non-HDL cholesterol in patients with type 2 diabetes and dyslipidemia(De Luis, DA 2009). • -3 fatty acids reduced plasma TG, total cholesterol without altering glycemic index (Sirtori CR, 1998).

  5. Mechanisms • TG-Lowering Effect • Reduced TG secretion • Increased TG clearance • Increased -oxidation

  6. Mechanisms Mediating the Cholesterol-Lowering Effects Cholesterol CYP 7A1 CYP 27A1 CYP 11A CYP 3A Cholesterol hydroxylation Bile acid PXR CYP3A Sult1e1 Sult2a1 Sult3e1 Gsta1 Gsta2 Sulfotransferases Glutathione S transferases Bile acid Detoxification

  7. Mechanisms Mediating the Anti-Inflammatory Effects of -3s • Interference with arachidonic acid metabolism • COX-derived 3-series eicosanoids • LOX-derived resolvins • Cytochrome P450-derived epoxides

  8. PXR and Inflammation PXR CYP 2C and CYP 3A -3 FAs -3 epoxides Anti-inflammatory

  9. PXR • Drug detoxification • Bile acid homeostasis • Cholesterol metabolism • Reduce inflammation

  10. Preliminary Data Effect of Fish Oil on Plasma Lipids n=13-15 per group; ^P<0.001 vs OO OO-Olive Oil, FO-Fish Oil

  11. Effect of Fish Oil on Hepatic Steatosis n=4-10 per group; ^P<0.001 vs OO OO-Olive Oil, FO-Fish Oil

  12. Effect of Fish Oil on Inflammatory Genes in Liver n=5-6 per group; ^P<0.001 and #P<0.01 vs OO OO-Olive Oil, FO-Fish Oil

  13. Genes Upregulated in Liver upon Fish Oil Feeding-Microarray Analysis

  14. Effect of Fish Oil on PXR and CYP3A in Liver OO,Olive Oil; FO, Fish Oil, n=5-6 samples per group, #P<0.01 vs OO

  15. Hypothesis Cholesterol-lowering Effects Cardioprotective Effects -3 Fatty Acids (EPA & DHA) PXR Anti-inflammatory Effects Overall Hypothesis: The cholesterol-lowering and anti-inflammatory effects of -3 fatty acids are mediated via PXR.

  16. Specific Aims Specific Aim 1: To determine the role of PXR in mediating the cholesterol-lowering and anti-inflammatory effects of -3 fatty acids in a model of diet-induced obesity and dyslipidemia. Specific Aim 2: To determine the role of PXR in mediating the cholesterol-lowering and anti-atherosclerotic effects of -3 fatty acids in a model of genetic dyslipidemia. Specific Aim 3: To determine whether the -3 fatty acids modulate PXR signaling in cultured hepatocytes.

  17. Experimental Design-Specific Aim 1 Experimental Diets High Fat Diet 45% Fat (energy) 1% Cholesterol Chow Diet Study Groups Mutant-PXR-/- WT-PXR+/+ Chow Diet 0.56% Oleic Acid 0.56% -3s Chow Diet 0.56% -3s 0.56% Oleic Acid

  18. Proposed Experiments-Specific Aim 1 • Lipid profiles in plasma and liver • Expression of genes/proteins involved in cholesterol/bile • acid metabolism and inflammatory response • Analysis of gall bladder bile for cholesterol and phospholipids • Levels of -3 epoxide metabolites in liver

  19. Experimental Design-Specific Aim 2 Experimental Diets High Fat Diet 40% Fat (energy) 0.5% Cholesterol Chow Diet Study Groups LDLR;PXR-/- LDLR-/- Chow Diet 0.56% Oleic Acid 0.56% -3s Chow Diet 0.56% -3s 0.56% Oleic Acid

  20. Proposed Experiments-Specific Aim 2 • Lipid profiles in plasma and liver • Genes involved in cholesterol/bile acid metabolism • and inflammatory response • Analysis of gall bladder bile for cholesterol and phospholipids • Atherosclerotic lesion area

  21. Experimental Design-Specific Aim 3 Primary Hepatocytes from WT and PXR-/- Mice PXR Signaling LCA+ -3s LCA Bile Acid Detoxification Bile Acid Detoxification Inflammation Inflammation Apoptosis Apoptosis

  22. Experimental Design-Specific Aim 3 Human HepG2 Cell Line Scrambled siRNA for PXR siRNA for PXR Inflammation  Inflammation  LCA -3s -3s Apoptosis  Apoptosis 

  23. Summary Genetic Dyslipidemia Dyslipidemia in Obesity -3 Fatty Acids (EPA & DHA) SA2 SA1 Hepatocyte Inflammation & Apoptosis PXR Signaling SA3 CYP 2C & CYP 3A Cholesterol & Bile Acid Metabolism 3-Epoxides Liver Anti-inflammatory Effects Lipid-lowering Effects Anti-atherosclerotic Effects

  24. Impact • Identification of novel molecular mechanisms by which -3 fatty acids mediate their cholesterol-lowering and anti-inflammatory effects. • The findings will be critical to target PXR using dietary factors to efficiently prevent/treat dyslipidemia in humans without adverse side effects.

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