DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

Summary

Principal Investigator: DONALD JUMP
Abstract: DESCRIPTION (provided by applicant): The molecular basis of dietary fatty acid regulation of gene expression has gained considerable attention in recent years because of its contribution to chronic disease [obesity, diabetes &atherosclerosis]: Our studies have focused on dietary polyunsaturated fatty acid (PUFA: eicosapentaenoic acid [20:5n3] and docosahexaneoic acid [22:6n3]) control of three hepatic transcription factors, sterol regulatory element binding protein (SREBP-1c), peroxisome proliferator activated receptor (PPARalpha) and liver X receptor (LXRalpha). These studies have revealed new information on: a) dynamic &cell-specific PUFA regulation of each transcription factor;b) developmental regulation of SREBP-1c and its regulatory network, and c) a role for PPARalpha and SREBP-1 in PUFA synthesis;d) the regulation of fatty acid elongases &desaturases;e) induction of these enzymes generates fatty acids that do not normally accumulate in cells;these rare fatty acids impact cell signaling by affecting eicosanoid production. These findings have broad implications for metabolic regulation, particularly with regard to chronic diseases like diabetes, obesity and atherosclerosis, where clinical data links fatty acid metabolites to disease progression. There remains a poor understanding of the role fatty acid elongases play in hepatic and whole body physiology. We hypothesize that hepatic fatty acid elongation: a) regulates hepatic &extrahepatic (aortic and blood) fatty acid composition;b)/egulates key transcription factors [PPARalpha &SREBP-1 c];and c) influences the onset or progression of chronic disease, e.g., diabetes, obesity or atherosclerosis. The specific aims are to: 1. Define the metabolic regulation of hepatic fatty acid elongases;2. Define the role of PPARalpha and SREBP-1 in the regulation of fatty acid elongases;3. Define the effects of fatty acid elongases on hepatocyte lipid composition and gene expression;4. Determine how over expression of specific fatty acid elongases affects hepatic function, blood lipid composition and the onset of chronic disease.
Funding Period: 1991-08-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc Vitamin E deficiency decreases long-chain PUFA in zebrafish (Danio rerio)
    Katie M Lebold
    Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
    J Nutr 141:2113-8. 2011
  2. pmc Growth hormone regulates the balance between bone formation and bone marrow adiposity
    Philip J Menagh
    Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA
    J Bone Miner Res 25:757-68. 2010
  3. pmc Role of fatty acid elongases in determination of de novo synthesized monounsaturated fatty acid species
    Christopher D Green
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 51:1871-7. 2010
  4. pmc Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese C57BL/6J mice
    Sasmita Tripathy
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
    J Lipid Res 51:2642-54. 2010
  5. pmc Fatty acid regulation of hepatic lipid metabolism
    Donald B Jump
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA
    Curr Opin Clin Nutr Metab Care 14:115-20. 2011
  6. pmc Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation
    Donald B Jump
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, United States
    Biochem Pharmacol 81:649-60. 2011
  7. pmc Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways
    Daniela Botolin
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 47:181-92. 2006
  8. pmc Remodeling of retinal Fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4
    Maria Tikhonenko
    Department of Physiology, Michigan State University, East Lansing, Michigan, USA
    Diabetes 59:219-27. 2010
  9. pmc Mammalian fatty acid elongases
    Donald B Jump
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
    Methods Mol Biol 579:375-89. 2009
  10. pmc Elevated insulin secretion from liver X receptor-activated pancreatic beta-cells involves increased de novo lipid synthesis and triacylglyceride turnover
    Christopher D Green
    Departments of Physiology, Michigan State University, East Lansing, Michigan 48824 3320, USA
    Endocrinology 150:2637-45. 2009

Scientific Experts

  • DONALD JUMP
  • Julia V Busik
  • Yun Wang
  • Weiqin Chen
  • Daniela Botolin
  • Barbara Christian
  • Christopher D Green
  • Jinghua Xu
  • Sasmita Tripathy
  • L Karl Olson
  • Katie M Lebold
  • Maria Tikhonenko
  • Philip J Menagh
  • Moises Torres-Gonzalez
  • Walter J Esselman
  • Charlotte L Wright
  • Carrie L Barton
  • Galen W Miller
  • Maret G Traber
  • Edwin M Labut
  • Robert L Tanguay
  • Clifford J Rosen
  • Gavin E Reid
  • Andrew Sochacki
  • Rebecca L Renis
  • Urszula T Iwaniec
  • Cansel G Ozguden-Akkoc
  • Timothy Kern
  • Carmen P Wong
  • Madalina Opreanu
  • Russell T Turner
  • Malcolm B Lowry
  • Shoshana Yakar
  • Todd A Lydic
  • Kelly M McSorley
  • Muraleedharan Nair
  • Jeffery M Peters
  • Bolleddula Jayaprakasam
  • Muraleedharan G Nair
  • Ernestine Mitchell
  • Jeffrey M Peters

Detail Information

Publications19

  1. pmc Vitamin E deficiency decreases long-chain PUFA in zebrafish (Danio rerio)
    Katie M Lebold
    Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
    J Nutr 141:2113-8. 2011
    ..Thus, inadequate vitamin E status led to a depletion of PUFA that may be a result of either or both increased lipid peroxidation and an impaired ability to synthesize sufficient PUFA, especially (n-3) PUFA...
  2. pmc Growth hormone regulates the balance between bone formation and bone marrow adiposity
    Philip J Menagh
    Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA
    J Bone Miner Res 25:757-68. 2010
    ..Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation...
  3. pmc Role of fatty acid elongases in determination of de novo synthesized monounsaturated fatty acid species
    Christopher D Green
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 51:1871-7. 2010
    ..Given the relative abundance of 16:0 to 16:1,n-7 and the specificity of Elovl-6 for 16:0, Elovl-6 is a major elongase for 18:1,n-9 production...
  4. pmc Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese C57BL/6J mice
    Sasmita Tripathy
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
    J Lipid Res 51:2642-54. 2010
    ..Our findings establish a link between fatty acid elongation and hepatic glucose metabolism and suggest a role for regulators of Elovl5 activity in the treatment of diet-induced hyperglycemia...
  5. pmc Fatty acid regulation of hepatic lipid metabolism
    Donald B Jump
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA
    Curr Opin Clin Nutr Metab Care 14:115-20. 2011
    ..To discuss transcriptional mechanisms regulating hepatic lipid metabolism...
  6. pmc Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation
    Donald B Jump
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, United States
    Biochem Pharmacol 81:649-60. 2011
    ..Pharmacological inhibition of ACC activity will not only attenuate DNL and induce FAO, but will also attenuate the synthesis of very long chain saturated, mono- and polyunsaturated fatty acids...
  7. pmc Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways
    Daniela Botolin
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 47:181-92. 2006
    ..Thus, 22:6,n-3 suppresses hepatocyte nSREBP-1 through 26S proteasome- and Erk-dependent pathways. These studies reveal a novel mechanism for n-3 PUFA regulation of hepatocyte nSREBP-1 and lipid metabolism...
  8. pmc Remodeling of retinal Fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4
    Maria Tikhonenko
    Department of Physiology, Michigan State University, East Lansing, Michigan, USA
    Diabetes 59:219-27. 2010
    ..However, there are no experimental data on retinal fatty acid metabolism in diabetes. This study determined retinal-specific fatty acid metabolism in control and diabetic animals...
  9. pmc Mammalian fatty acid elongases
    Donald B Jump
    Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
    Methods Mol Biol 579:375-89. 2009
    ..Herein, methods are described to measure elongase activity, analyze elongation products, and alter cellular elongase expression...
  10. pmc Elevated insulin secretion from liver X receptor-activated pancreatic beta-cells involves increased de novo lipid synthesis and triacylglyceride turnover
    Christopher D Green
    Departments of Physiology, Michigan State University, East Lansing, Michigan 48824 3320, USA
    Endocrinology 150:2637-45. 2009
    ....
  11. pmc N-3 polyunsaturated fatty acid regulation of hepatic gene transcription
    Donald B Jump
    Department of Nutrition and Exercise Sciences, Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331 5109, USA
    Curr Opin Lipidol 19:242-7. 2008
    ..This review brings together metabolic and molecular studies that help explain n-3 (omega-3) polyunsaturated fatty acid regulation of hepatic gene transcription...
  12. pmc Elevated hepatic fatty acid elongase-5 activity affects multiple pathways controlling hepatic lipid and carbohydrate composition
    Yun Wang
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 49:1538-52. 2008
    ..As such, hepatic Elovl5 activity may affect hepatic glucose production during fasting. In summary, Elovl5-induced changes in hepatic fatty acid content affect multiple pathways regulating hepatic lipid and carbohydrate composition...
  13. pmc Docosahexaenoic acid (DHA) and hepatic gene transcription
    Donald B Jump
    Department of Physiology, Michigan State University, East Lansing, MI 48824, United States
    Chem Phys Lipids 153:3-13. 2008
    ..22:6,n-3 control of these same signaling pathways in non-hepatic tissues may help to explain the diverse actions of n-3 PUFA on such complex physiological processes as visual acuity and learning...
  14. pmc Inhibition of cytokine signaling in human retinal endothelial cells through modification of caveolae/lipid rafts by docosahexaenoic acid
    Weiqin Chen
    Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824, USA
    Invest Ophthalmol Vis Sci 48:18-26. 2007
    ....
  15. pmc Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity
    Yun Wang
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 47:2028-41. 2006
    ..In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition...
  16. pmc Regulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-alpha agonist
    Jinghua Xu
    Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA
    J Biol Chem 281:18351-62. 2006
    ..In conclusion, n-3 PUFA and WY14643/PPARalpha target different transcription factors to control L-PK gene transcription. MLX, the heterodimer partner for ChREBP, has emerged as a novel target for n-3 PUFA regulation...
  17. ncbi Fatty acid regulation of hepatic gene transcription
    Donald B Jump
    Departments of Physiology, Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
    J Nutr 135:2503-6. 2005
    ..Many of these mechanisms are regulated by PPARalpha or SREBP-1c. Together, these mechanisms control hepatic lipid composition and affect whole-body lipid composition...
  18. pmc Anti-inflammatory effect of docosahexaenoic acid on cytokine-induced adhesion molecule expression in human retinal vascular endothelial cells
    Weiqin Chen
    Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, 48824, USA
    Invest Ophthalmol Vis Sci 46:4342-7. 2005
    ..Despite the importance of vascular inflammation in diabetic retinopathy, the anti-inflammatory role of DHA(22:6n3) in cytokine-stimulated human retinal vascular endothelial cells (hRVECs) has not been addressed...
  19. pmc Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases
    Yun Wang
    Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
    J Lipid Res 46:706-15. 2005
    ..In conclusion, changes in Elovl-5 expression may account for much of the nutritional and developmental control of fatty acid elongation activity in the rat liver...