본문 바로가기
KERD
논문KCI 등재

Folic acid supplementation prevents high fructose-induced non-alcoholic fatty liver disease by activating the AMPK and LKB1 signaling pathways

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

초록

BACKGROUND/OBJECTIVES: The present study aimed to evaluate the effects of folic acid supplementation in high-fructose-induced hepatic steatosis and clarify the underlying mechanism of folic acid supplementation. MATERIALS/METHODS: Male SD rats were fed control, 64% high-fructose diet, or 64% high-fructose diet with folic acid for eight weeks. Plasma glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lipid profiles, hepatic lipid content, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured. RESULTS: The HF diet significantly increased hepatic total lipid and triglyceride (TG) and decreased hepatic SAM, SAH, and SAM:SAH ratio. In rats fed a high fructose diet, folic acid supplementation significantly reduced hepatic TG, increased hepatic SAM, and alleviated hepatic steatosis. Moreover, folic acid supplementation in rats fed high fructose enhanced the levels of phosphorylated AMP-activated protein kinase (AMPK) and liver kinase B (LKB1) and inhibited phosphorylation of acetyl coenzyme A carboxylase (ACC) in the liver. CONCLUSIONS: These results suggest that the protective effect of folic acid supplementation in rats fed high fructose may include the activation of LKB1/AMPK/ACC and increased SAM in the liver, which inhibit hepatic lipogenesis, thus ameliorating hepatic steatosis. The present study may provide evidence for the beneficial effects of folic acid supplementation in the treatment of non-alcoholic fatty liver disease.

Abstract

BACKGROUND/OBJECTIVES: The present study aimed to evaluate the effects of folic acid supplementation in high-fructose-induced hepatic steatosis and clarify the underlying mechanism of folic acid supplementation. MATERIALS/METHODS: Male SD rats were fed control, 64% high-fructose diet, or 64% high-fructose diet with folic acid for eight weeks. Plasma glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lipid profiles, hepatic lipid content, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured. RESULTS: The HF diet significantly increased hepatic total lipid and triglyceride (TG) and decreased hepatic SAM, SAH, and SAM:SAH ratio. In rats fed a high fructose diet, folic acid supplementation significantly reduced hepatic TG, increased hepatic SAM, and alleviated hepatic steatosis. Moreover, folic acid supplementation in rats fed high fructose enhanced the levels of phosphorylated AMP-activated protein kinase (AMPK) and liver kinase B (LKB1) and inhibited phosphorylation of acetyl coenzyme A carboxylase (ACC) in the liver. CONCLUSIONS: These results suggest that the protective effect of folic acid supplementation in rats fed high fructose may include the activation of LKB1/AMPK/ACC and increased SAM in the liver, which inhibit hepatic lipogenesis, thus ameliorating hepatic steatosis. The present study may provide evidence for the beneficial effects of folic acid supplementation in the treatment of non-alcoholic fatty liver disease.

참고문헌 (44)

  1. Chitturi S, "Nonalcoholic fatty liver in Asia : firmly entrenched and rapidly gaining ground", J Gastroenterol Hepatol, 26(Suppl 1), pp.163~172 (2011)
  2. McCullough AJ, "The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease", Clin Liver Dis, 8, pp.521~533 (2004)
  3. Brunt EM, "Nonalcoholic steatohepatitis : a proposal for grading and staging the histological lesions", Am J Gastroenterol, 94, pp.2467~2474 (1999)
  4. Söderberg C, "Decreased survival of subjects with elevated liver function tests during a 28-year follow-up", Hepatology, 51, pp.595~602 (2010)
  5. Dajani A, "Treatment of nonalcoholic fatty liver disease : where do we stand? An overview", Saudi J Gastroenterol, 22, pp.91~105 (2016)
  6. Nicole Fakhoury-Sayegh, "Characteristics of nonalcoholic fatty liver disease induced in wistar rats following four different diets", Nutrition Research and Practice, 9(4), pp.350~357 (2015), 한국영양학회[DOI]
  7. Kawasaki T, "Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis", J Nutr, 139, pp.2067~2071 (2009)
  8. Mayes PA, "Intermediary metabolism of fructose", Am J Clin Nutr, 58, pp.754~ (1993)
  9. Commerford SR, "Diets enriched in sucrose or fat increase gluconeogenesis and G-6-Pase but not basal glucose production in rats", Am J Physiol Endocrinol Metab, 283, pp.E545~E555 (2002)
  10. Dirlewanger M, "Effects of fructose on hepatic glucose metabolism in humans", Am J Physiol Endocrinol Metab, 279, pp.E907~E911 (2000)
  11. Pagliassotti MJ, "Glucose-6-phosphatase activity is not suppressed but the mRNA level is increased by a sucrose-enriched meal in rats", J Nutr, 133, pp.32~37 (2003)
  12. Basciano H, "Fructose, insulin resistance, and metabolic dyslipidemia", Nutr Metab(Lond), 2, pp.5~ (2005)
  13. Ajiboye TO, "Dioscoreophyllum cumminsii(Stapf)Diels leaves halt high-fructose induced metabolic syndrome : hyperglycemia, insulin resistance, inflammation and oxidative stress", J Ethnopharmacol, 192, pp.471~479 (2016)
  14. Robinson K, "Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease", Circulation, 92, pp.2825~2830 (1995)
  15. Mansoor MA, "Dynamic relation between reduced, oxidized, and protein-bound homocysteine and other thiol components in plasma during methionine loading in healthy men", Clin Chem, 38, pp.1316~1321 (1992)
  16. Suliman ME, "Effects of methionine loading on plasma and erythrocyte sulphur amino acids and sulph-hydryls before and after co-factor supplementation in haemodialysis patients", Nephrol Dial Transplant, 16, pp.102~110 (2001)
  17. Noureddin M, "Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine", Exp Biol Med(Maywood), 240, pp.809~820 (2015)
  18. Dahlhoff C, "Methyl-donor supplementation in obese mice prevents the progression of NAFLD, activates AMPK and decreases acyl-carnitine levels", Mol Metab, 3, pp.565~580 (2014)
  19. Cantó C, "AMP-activated protein kinase and its downstream transcriptional pathways", Cell Mol Life Sci, 67, pp.3407~3423 (2010)
  20. Woods A, "Liver-specific activation of AMPK prevents steatosis on a high-fructose diet", Cell Reports, 18, pp.3043~3051 (2017)
  21. Chang HC, "SIRT1 and other sirtuins in metabolism", Trends Endocrinol Metab, 25, pp.138~145 (2014)
  22. Buettner R, "Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome", Horm Metab Res, 42, pp.769~774 (2010)
  23. Sid V, "Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism", Am J Physiol Regul Integr Comp Physiol, 309, pp.R1215~R1225 (2015)
  24. National Research Council (US) Subcommittee on Laboratory Animal Nutrition, "Nutrient Requirements of Laboratory Animals" (1995), National Academies Press
  25. Reeves PG, "Components of the AIN-93 diets as improvements in the AIN-76A diet", J Nutr, 127, pp.838S~841S (1997)
  26. Wagner J, "A rapid high-performance liquid chromatographic procedure for the simultaneous determination of methionine, ethionine, S-adenosylmethionine, S-adenosylethionine, and the natural polyamines in rat tissues", Anal Biochem, 140, pp.108~116 (1984)
  27. Folch J, "A simple method for the isolation and purification of total lipides from animal tissues", J Biol Chem, 226, pp.497~509 (1957)
  28. Sanders MJ, "Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade", Biochem J, 403, pp.139~148 (2007)
  29. "Carrot Juice Administration Decreases Liver Stearoyl-CoA Desaturase 1 and Improves Docosahexaenoic Acid Levels, But Not Steatosis in High Fructose Diet-Fed Weanling Wistar Rats", Preventive Nutrition and Food Science, 21(3), pp.171~180 (2016), 한국식품영양과학회[DOI]
  30. Bergheim I, "Antibiotics protect against fructose-induced hepatic lipid accumulation in mice : role of endotoxin", J Hepatol, 48, pp.983~992 (2008)
  31. Weiß J, "Non-alcoholic fatty liver disease : epidemiology, clinical course, investigation, and treatment", Dtsch Arztebl Int, 111, pp.447~452 (2014)
  32. Agren JJ, "Isolation of very low density lipoprotein phospholipids enriched in ethanolamine phospholipids from rats injected with Triton WR 1339", Biochim Biophys Acta, 1734, pp.34~43 (2005)
  33. Jonas A, "Biochemistry of Lipids, Lipoproteins and Membranes", pp.485~506 (2008), Elsevier Science
  34. Cano A, "Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice", Hepatology, 54, pp.1975~1986 (2011)
  35. Hardie DG, "Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase", Biochem Soc Trans, 30, pp.1064~1070 (2002)
  36. Hudson ER, "A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias", Curr Biol, 13, pp.861~866 (2003)
  37. Shackelford DB, "The LKB1-AMPK pathway : metabolism and growth control in tumour suppression", Nat Rev Cancer, 9, pp.563~575 (2009)
  38. Anderson KA, "Hypothalamic CaMKK2 contributes to the regulation of energy balance", Cell Metab, 7, pp.377~388 (2008)
  39. Tamás P, "Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes", J Exp Med, 203, pp.1665~1670 (2006)
  40. Stahmann N, "Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+", calmodulin-dependent protein kinase kinase β, 2006, pp.26, 5933~5945
  41. Hawley SA, "Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase", Cell Metab, 2, pp.9~19 (2005)
  42. Ha J, "Critical phosphorylation sites for acetyl-CoA carboxylase activity", J Biol Chem, 269, pp.22162~22168 (1994)
  43. Wang Q, "AMPK-mediated regulation of lipid metabolism by phosphorylation", Biol Pharm Bull, 41, pp.985~993 (2018)
  44. Park SH, "Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle", J Appl Physiol(1985), 92, pp.2475~2482 (2002)

관련 논문AI추천

이 간행물의 다른 논문 (10건)