Caloric Restriction-Mediated Induction of Lipid Metabolism Gene Expression in Liver is Enhanced by Keap1-Knockdown
- 521 Downloads
CR increases fatty acid oxidation to decrease tissue lipid content. The Nuclear factor E2-related factor 2 (Nrf2)-Kelch like ECH associated Protein 1 (Keap1) pathway is an antioxidant gene regulatory pathway that has been previously investigated in weight gain. However, limited interaction of Nrf2/Keap1 and CR exists. The purpose of this study was to determine how Keap1 knockdown (Keap1-KD), which is known to increase Nrf2 activity, affects the CR response, such as weight loss, hepatic lipid decrease, and induction of fatty acid oxidation gene expression.
C57BL/6 and Keap1-KD mice were maintained on 40% CR or fed ad libitum for 6 weeks. Hepatic lipid content, lipid metabolic gene, and miRNA expression was quantified.
CR lowered hepatic lipid content, and induced fatty acid oxidation gene expression to a greater degree in Keap1-KD compared to C57BL/6 mice. CR differentially altered miRNA 34a, 370, let-7b* in livers of Keap1-KD compared to C57BL/6 mice.
CR induced induction of fatty acid oxidation gene expression was augmented with Keap1 knockdown, which was associated with differential expression of several miRNAs implicated in fatty acid oxidation and lipid accumulation.
KEY WORDScaloric restriction gene expression liver Nfe2l2 nuclear receptor
Acyl-CoA thioesterase 1
Carnitine palmitoyltransferase 1A
Fatty acid binding protein 4
Fatty acid synthase
Farnesoid X receptor
Glutamate cysteine ligase catalytic subunit, and
Kelch like ECH-associated Protein 1
Liver x receptor
Non-alcoholic fatty liver disease
NAD(P) H:quinone oxidoreductase
Nuclear factor E2-Related factor 2
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
Peroxisome Proliferator activated receptor α
RNA induced silencing complex
Sterol regulatory element binding protein 1c
- 5.McWalter GK, Higgins LG, McLellan LI, Henderson CJ, Song L, Thornalley PJ, et al. Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr. 2004;134:3499S–506S.PubMedGoogle Scholar
- 6.Kay HY, Kim WD, Hwang SJ, Choi HS, Gilroy RK, Wan YJ, et al. Nrf2 inhibits LXRalpha-dependent hepatic lipogenesis by competing with FXR for acetylase binding. Antioxid Redox Signal. 2011;15:2135–2146.Google Scholar
- 11.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–609.PubMedCrossRefGoogle Scholar
- 12.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.PubMedCrossRefGoogle Scholar
- 29.Leeand J, Kemper JK. Controlling SIRT1 expression by microRNAs in health and metabolic disease. Aging (Albany NY). 2010;2:527–34.Google Scholar
- 44.Lee, AP, Sharma A, Song G, Miao J, Mo YY, Wang L, et al. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. The J Biol Chem. 2010;285:12604–12611Google Scholar
- 45.Castro RE, Ferreira DM, Afonso MB, Borralho PM, Machado MV, Cortez-Pinto H, et al. miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease. J Hepatol. 2013;58(1):119–25Google Scholar
- 46.More VR, Xu J, Shimpi PC, Belgrave C, Luyendyk JP, Yamamoto M, et al. Keap1 knockdown increases markers of metabolic syndrome after long-term fat diet feeding. Free Radic Biol Med. 2013.Google Scholar
- 54.Frostand RJ, Olson EN. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc Natl Acad Sci USA. 2011;108:21075–21080Google Scholar
- 57.Wu KC, Liu J, Klaassen CD. Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation. Toxicol Appl Pharmacol. 2012;262:321–329.Google Scholar