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.

Public Health Relevance

Dietary polyunsaturated fatty acids (PUFA) are generally regarded as beneficial to human health and well being. Obese humans with diabetes, metabolic syndrome or non-alcoholic fatty liver disease have impaired PUFA metabolism. We have linked hepatic PUFA synthesis to the control of hepatic triglycerides and stress pathways that impact fasting blood glucose. Further study of this novel mechanism will lead to better methods to control hepatic metabolism and diabetic complications.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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Oregon State University
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Jump, Donald B; Lytle, Kelli A; Depner, Christopher M et al. (2018) Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease. Pharmacol Ther 181:108-125
Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita et al. (2016) Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr-/- mice. Proc Nutr Soc 75:1-9
Lytle, Kelli A; Jump, Donald B (2016) Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible? PLoS One 11:e0146942
Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita et al. (2015) Potential for dietary ?-3 fatty acids to prevent nonalcoholic fatty liver disease and reduce the risk of primary liver cancer. Adv Nutr 6:694-702
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Tripathy, Sasmita; Lytle, Kelli A; Stevens, Robert D et al. (2014) Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice. J Lipid Res 55:1448-64
Depner, Christopher M; Traber, Maret G; Bobe, Gerd et al. (2013) A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice. PLoS One 8:e83756
Lebold, Katie M; Kirkwood, Jay S; Taylor, Alan W et al. (2013) Novel liquid chromatography-mass spectrometry method shows that vitamin E deficiency depletes arachidonic and docosahexaenoic acids in zebrafish (Danio rerio) embryos. Redox Biol 2:105-13
Jump, Donald B; Tripathy, Sasmita; Depner, Christopher M (2013) Fatty acid-regulated transcription factors in the liver. Annu Rev Nutr 33:249-69

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