PUFA Synthesis and the Control of Hepatic Metabolism

Summary

Principal Investigator: Donald B Jump
Abstract: DESCRIPTION (provided by applicant): Dietary polyunsaturated fatty acids (PUFA) are generally regarded as beneficial to human health. Obese humans with diabetes (NIDDM), metabolic syndrome (MetS) or non-alcoholic fatty liver disease (NAFLD), however, have low a low ratio of 20:4w6 relative to 18:2w6 in plasma and liver when compared to healthy individuals. This outcome implicates a problem with PUFA metabolism. While the linkage between PUFA metabolism and diabetic complications in humans is unclear, recent studies with diet-induced obese-diabetic mice have established a link between PUFA synthesis and diabetic complications. We reported that the activity of hepatic fatty acid elongase-5 (Elovl5), a key enzyme involved in PUFA synthesis, was suppressed in livers of diet-induced obese-diabetic C57BL/6J mice. Restoration of hepatic Elovl5 activity abrogated high fat diet-induced hyperglycemia, insulin resistance, and fatty liver in 4 days without changing body weight or appetite. The mechanism for the control of blood glucose was linked to the suppression of hepatic nuclear content of forkhead box O1 (FoxO1), a major transcription factor controlling gluconeogenesis (GNG). Elevated Elovl5 activity increased the phosphorylation and acetylation status of FoxO1 and attenuated the expression of genes involved in GNG, e.g., phosphoenolpyruvate carboxykinase and glucose-6 phosphatase. Preliminary studies show that Elovl5 controls FoxO1 phosphorylation through the mTorc2 (rictor)-Akt2 pathway. Moreover, elevated Elovl5 activity induced adipocyte triglyceride lipase (ATGL), comparative gene identification-58 (CGI58, ATGL co-activator) and short &long chain acylcarnitines in livers of obese mice. This outcome suggests Elovl5 activity controls hepatic triglyceride (TAG) by regulating TAG hydrolysis and fatty acid oxidation (FAO). Finally, elevated hepatic Elovl5 activity attenuated stress pathways ([ER-stress, XBP1 and ATF6];NFkB, Jnk &p38) and induced the anti-oxidant enzyme, i.e., hemeoxygenase-1 (HMOX1). Both ER- and oxidant stress control FoxO1 and GNG. This grant proposal will provide additional mechanistic insight to explain how hepatic PUFA synthesis controls FoxO1, GNG, TAG metabolism and stress pathways. Using cultured hepatocytes and obese-diabetic mice, Aim 1 will define how endogenously generated and exogenously supplied PUFA control hepatic FoxO1, GNG, TAG and stress pathways. Aim 2 will establish the requirement for ATGL and CGI58 in the Elovl5 control of hepatic TAG &FoxO1, GNG and anti-oxidant-response pathways (HMOX1). Aim 3 will establish the requirement for HMOX1 and other anti-oxidant enzymes in the Elovl5 control of FoxO1, GNG, ATGL, CGI58 and TAG. Defining the mechanistic linkage between PUFA synthesis, TAG hydrolysis, FoxO1, GNG &stress pathways will identify novel methods to manage diabetic complications, like hyperglycemia &fatty liver.
Funding Period: 2012-04-01 - 2016-03-31
more information: NIH RePORT

Top Publications

  1. pmc Omega-3 fatty acid supplementation and cardiovascular disease
    Donald B Jump
    Nutrition Program, School of Biological and Population Health Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
    J Lipid Res 53:2525-45. 2012
  2. pmc Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice
    Sasmita Tripathy
    Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
    J Lipid Res 54:71-84. 2013
  3. pmc Docosahexaenoic acid attenuates hepatic inflammation, oxidative stress, and fibrosis without decreasing hepatosteatosis in a Ldlr(-/-) mouse model of western diet-induced nonalcoholic steatohepatitis
    Christopher M Depner
    The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
    J Nutr 143:315-23. 2013
  4. pmc Fatty acid-regulated transcription factors in the liver
    Donald B Jump
    Nutrition Program, School of Biological and Population Health Science, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
    Annu Rev Nutr 33:249-69. 2013
  5. pmc A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice
    Christopher M Depner
    The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America
    PLoS ONE 8:e83756. 2013
  6. ncbi Novel liquid chromatography-mass spectrometry method shows that vitamin E deficiency depletes arachidonic and docosahexaenoic acids in zebrafish (Danio rerio) embryos
    Katie M Lebold
    Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331, USA
    Redox Biol 2:105-13. 2013

Detail Information

Publications6

  1. pmc Omega-3 fatty acid supplementation and cardiovascular disease
    Donald B Jump
    Nutrition Program, School of Biological and Population Health Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
    J Lipid Res 53:2525-45. 2012
    ..The outcome of our analysis reveals that nonfish sources of ω 3 PUFA vary in their capacity to regulate blood levels of C(20-22) ω 3 PUFA and CVD risk factors...
  2. pmc Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice
    Sasmita Tripathy
    Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
    J Lipid Res 54:71-84. 2013
    ..These results establish a novel link between Elovl5-mediated synthesis of 18:1,n-7 and GNG through the control of the mTORC2-Akt-FoxO1 pathway...
  3. pmc Docosahexaenoic acid attenuates hepatic inflammation, oxidative stress, and fibrosis without decreasing hepatosteatosis in a Ldlr(-/-) mouse model of western diet-induced nonalcoholic steatohepatitis
    Christopher M Depner
    The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
    J Nutr 143:315-23. 2013
    ..Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans...
  4. pmc Fatty acid-regulated transcription factors in the liver
    Donald B Jump
    Nutrition Program, School of Biological and Population Health Science, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
    Annu Rev Nutr 33:249-69. 2013
    ..Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. ..
  5. pmc A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice
    Christopher M Depner
    The Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America
    PLoS ONE 8:e83756. 2013
    ..Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR(-/-) mice...
  6. ncbi Novel liquid chromatography-mass spectrometry method shows that vitamin E deficiency depletes arachidonic and docosahexaenoic acids in zebrafish (Danio rerio) embryos
    Katie M Lebold
    Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR 97331, USA
    Redox Biol 2:105-13. 2013
    ..Vitamin E deficiency during embryogenesis depleted DHA and arachidonic acid, and increased hydroxy-fatty acids derived from these PUFA, suggesting that α-tocopherol is necessary to protect these critical fatty acids. ..

Research Grants30

  1. MAP Kinase Phosphatase 3 (MKP-3) and Obesity-related Gluconeogenesis
    Haiyan Xu; Fiscal Year: 2013
    ....
  2. Role of Chromogranin A in Metabolic Syndrome
    Sushil K Mahata; Fiscal Year: 2013
    ..2. Evaluate the potential therapeutic effects of CST and its variants on insulin sensitivity and baroreflex sensitivity and heart rate variability in high fat diet-induced insulin resistant and in db/db diabetic mice. ..
  3. The Role of Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease
    Jeffrey D Browning; Fiscal Year: 2013
    ....
  4. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
    Varman T Samuel; Fiscal Year: 2013
    ....