Generic placeholder image

Current Aging Science

Editor-in-Chief

ISSN (Print): 1874-6098
ISSN (Online): 1874-6128

Research Article

The Impact of Prolonged and Intermittent Fasting on PGC-1α, Oct-4, and CK-19 Liver Gene Expression

Author(s): Radiana Dhewayani Antarianto*, Marcello Mikhael Kadharusman, Shefilyn Wijaya and Novi Silvia Hardiny

Volume 16, Issue 1, 2023

Published on: 29 September, 2022

Page: [49 - 55] Pages: 7

DOI: 10.2174/1874609815666220627155337

Price: $65

Abstract

Background: Liver stemness refers to the high regenerative capacity of the organ. This intrinsic regeneration capacity allows the restoration of post-resection liver function in up to 50% of liver donors. Liver cirrhosis is one of the terminal liver diseases with a defect in the intrinsic regeneration capacity. Several attempts to restore intrinsic regeneration capacity by conducting in vivo studies on stem cells in various organs have shown the positive impact of fasting on stemness. An increased capacity for stem cell proliferation and regeneration was reported due to fasting. Prolonged fasting (PF) has been reported to maintain the long-term proliferative ability of hematopoietic stem cells. However, clinical trials on intermittent fasting (IF) have not conclusively given positive results for fasting individuals.

Objectives: This research aims to investigate the effect of fasting on liver stemness by comparing the expression of octamer-binding transcription factor 4 (Oct-4), cytokeratin 19 (CK-19), and peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) in liver cells of fasted rabbits with rabbits fed ad libitum. This study compares two types of fasting, which are intermittent (16 hours) and prolonged (40 hours) fasting, for liver stemness and intrinsic regenerative capacity.

Methods: A total of 18 rabbits were conditioned into 3 different groups. The first group was subjected to an ad libitum diet, the second to intermittent fasting (16-hour fasting), and the third to prolonged fasting (40-hour fasting). Afterward, the RNA was extracted from the liver tissues of each rabbit and analyzed via real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Relative expression was calculated using the Livak method.

Results: Compared to the ad libitum diet, a greater increase was reported in PGC-1α, upregulated Oct4, and steady CK-19 gene expressions in the livers of intermittent fasting rabbits. Prolonged fasting increased PGC1α, reduced liver stemness, and a statistically insignificant decrease in intrinsic liver regenerative capacity.

Conclusion: Intermittent fasting indicates preferable molecular alterations in liver stemness and intrinsic regenerative capacity compared to prolonged fasting.

Keywords: liver, stemness; Oct-4, CK-19, PGC-1α, fasting

[1]
Mokdad AA, Lopez AD, Shahraz S. et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: A systematic analysis. BMC Med 2014; 12(1): 145.
[http://dx.doi.org/10.1186/s12916-014-0145-y] [PMID: 25242656]
[2]
Kim WR, Lake JR, Smith JM. et al. OPTN/SRTR 2017 annual data report: Liver. Am J Transplant 2019; 19 (Suppl. 2): 184-283.
[http://dx.doi.org/10.1111/ajt.15276] [PMID: 30811890]
[3]
Piper MDW, Partridge L, Raubenheimer D, Simpson SJ. Dietary restriction and aging: A unifying perspective. Cell Metab 2011; 14(2): 154-60.
[http://dx.doi.org/10.1016/j.cmet.2011.06.013] [PMID: 21803286]
[4]
Colman RJ, Anderson RM, Johnson SC. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325(5937): 201-4.
[http://dx.doi.org/10.1126/science.1173635] [PMID: 19590001]
[5]
Jiang JC, Jaruga E, Repnevskaya MV, Jazwinski SM. An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J 2000; 14(14): 2135-7.
[http://dx.doi.org/10.1096/fj.00-0242fje] [PMID: 11024000]
[6]
Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev 2017; 39: 46-58.
[http://dx.doi.org/10.1016/j.arr.2016.10.005] [PMID: 27810402]
[7]
Cheng CW, Adams GB, Perin L. et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 2014; 14(6): 810-23.
[http://dx.doi.org/10.1016/j.stem.2014.04.014] [PMID: 24905167]
[8]
Ishikawa M, Saito K, Urata M, Kumagai Y, Maekawa K, Saito Y. Comparison of circulating lipid profiles between fasting humans and three animal species used in preclinical studies: Mice, rats and rabbits. Lipids Health Dis 2015; 14(104): 104.
[http://dx.doi.org/10.1186/s12944-015-0104-4] [PMID: 26358237]
[9]
Austin S, St-Pierre J. PGC1α and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 2012; 125(Pt 21): 4963-71.
[http://dx.doi.org/10.1242/jcs.113662] [PMID: 23277535]
[10]
Herzig S, Long F, Jhala US. et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 2001; 413(6852): 179-83.
[http://dx.doi.org/10.1038/35093131] [PMID: 11557984]
[11]
Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2011; 93(4): 884S-90.
[http://dx.doi.org/10.3945/ajcn.110.001917] [PMID: 21289221]
[12]
Puigserver P, Rhee J, Donovan J. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 2003; 423(6939): 550-5.
[http://dx.doi.org/10.1038/nature01667] [PMID: 12754525]
[13]
Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 1990; 60(3): 461-72.
[http://dx.doi.org/10.1016/0092-8674(90)90597-8] [PMID: 1967980]
[14]
Schöler HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P. New type of POU domain in germ line-specific protein Oct-4. Nature 1990; 344(6265): 435-9.
[http://dx.doi.org/10.1038/344435a0] [PMID: 1690859]
[15]
Rosner MH, Vigano MA, Ozato K. et al. A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 1990; 345(6277): 686-92.
[http://dx.doi.org/10.1038/345686a0] [PMID: 1972777]
[16]
Wu G, Schöler HR. Role of Oct4 in the early embryo development. Cell Regen (Lond) 2014; 3(1): 7.
[http://dx.doi.org/10.1186/2045-9769-3-7] [PMID: 25408886]
[17]
Park MR, Wong MS, Araúzo-Bravo MJ. et al. Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model. PLoS One 2019; 14(8): 1-20.
[http://dx.doi.org/10.1371/journal.pone.0221085]
[18]
Van Haele M, Snoeck J, Roskams T. Human Liver regeneration: An etiology dependent process. Int J Mol Sci 2019; 20(9): 2332.
[http://dx.doi.org/10.3390/ijms20092332] [PMID: 31083462]
[19]
Junge N, Sharma AD, Ott M. About cytokeratin 19 and the drivers of liver regeneration. J Hepatol 2017; 6: 7-9.
[PMID: 29031907]
[20]
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3(6): 1101-8.
[http://dx.doi.org/10.1038/nprot.2008.73] [PMID: 18546601]
[21]
Yoon JC, Puigserver P, Chen G. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413(6852): 131-8.
[http://dx.doi.org/10.1038/35093050] [PMID: 11557972]
[22]
Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 2000; 106(7): 847-56.
[http://dx.doi.org/10.1172/JCI10268] [PMID: 11018072]
[23]
Sokolović M, Sokolović A, Wehkamp D. et al. The transcriptomic signature of fasting murine liver. BMC Genomics 2008; 9(1): 528.
[http://dx.doi.org/10.1186/1471-2164-9-528] [PMID: 18990241]
[24]
Piccinin E, Arconzo M, Graziano G. et al. Hepatic microRNA expression by pgc-1α and pgc-1β in the mouse. Int J Mol Sci 2019; 20(22): 5735.
[http://dx.doi.org/10.3390/ijms20225735] [PMID: 31731670]
[25]
Tan Z, Luo X, Xiao L. et al. The role of pgc1α in cancer metabolism and its therapeutic implications. Mol Cancer Ther 2016; 15(5): 774-82.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0621] [PMID: 27197257]
[26]
Anton SD, Moehl K, Donahoo WT. et al. Flipping the metabolic switch: Understanding and applying the health benefits of fasting. Obesity (Silver Spring) 2018; 26(2): 254-68.
[http://dx.doi.org/10.1002/oby.22065] [PMID: 29086496]
[27]
Trepanowski JF, Kroeger CM, Barnosky A. et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: A randomized clinical trial. JAMA Intern Med 2017; 177(7): 930-8.
[http://dx.doi.org/10.1001/jamainternmed.2017.0936] [PMID: 28459931]
[28]
Harder-Lauridsen NM, Nielsen ST, Mann SP. et al. The effect of alternate-day caloric restriction on the metabolic consequences of 8 days of bed rest in healthy lean men: A randomized trial. J Appl Physiol 2017; 122(2): 230-41.
[http://dx.doi.org/10.1152/japplphysiol.00846.2016] [PMID: 27881670]
[29]
Sokolović M, Wehkamp D, Sokolović A. et al. Fasting induces a biphasic adaptive metabolic response in murine small intestine. BMC Genomics 2007; 8(1): 361.
[http://dx.doi.org/10.1186/1471-2164-8-361] [PMID: 17925015]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy