Open Access

Pressure suppresses hepatocellular glycogen synthesis through activating the p53/Pten pathway

  • Authors:
    • Junwei Shen
    • Yunchen Sun
    • Si Shen
    • Xu Luo
    • Jie Chen
    • Liang Zhu
  • View Affiliations

  • Published online on: April 19, 2019     https://doi.org/10.3892/mmr.2019.10177
  • Pages: 5105-5114
  • Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Portal hypertension is the primary cause of complications in patients with chronic liver diseases, and markedly impacts metabolism within the nervous system. Until recently, the role of portal hypertension in hepatocellular metabolism was unclear. The present study demonstrated that an increase in extracellular pressure significantly decreased hepatocellular glycogen concentrations in HepG2 and HL‑7702 cells. In addition, it reduced glycogen synthase activity, by inhibiting the phosphorylation of glycogen synthase 1. RNA‑seq analysis revealed that mechanical pressure suppressed glycogen synthesis by activating the p53/phosphatase and tensin homolog pathway, further suppressing glycogen synthase activity. The present study revealed an association between mechanical pressure and hepatocellular glycogen metabolism, and identified the regulatory mechanism of glycogen synthesis under pressure.

References

1 

Nestor-Bergmann A, Goddard G and Woolner S: Force and the spindle: Mechanical cues in mitotic spindle orientation. Semin Cell Dev Biol. 34:133–139. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Lesman A, Notbohm J, Tirrell DA and Ravichandran G: Contractile forces regulate cell division in three-dimensional environments. J Cell Biol. 205:155–162. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Harada S and Rodan GA: Control of osteoblast function and regulation of bone mass. Nature. 423:349–355. 2003. View Article : Google Scholar : PubMed/NCBI

4 

Robling AG, Castillo AB and Turner CH: Biomechanical and molecular regulation of bone remodeling. Annu Rev Biomed Eng. 8:455–498. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Bin G, Cuifang W, Bo Z, Jing W, Jin J, Xiaoyi T, Cong C, Yonggang C, Liping A, Jinglin M and Yayi X: Fluid shear stress inhibits TNF-α-induced osteoblast apoptosis via ERK5 signaling pathway. Biochem Biophys Res Commun. 466:117–123. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Caiazzo M, Okawa Y, Ranga A, Piersigilli A, Tabata Y and Lutolf MP: Defined three-dimensional microenvironments boost induction of pluripotency. Nat Mater. 15:344–352. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Altman GH, Horan RL, Martin I, Farhadi J, Stark PR, Volloch V, Richmond JC, Vunjak-Novakovic G and Kaplan DL: Cell differentiation by mechanical stress. ASEB J. 16:270–272. 2002.

8 

Estes BT, Gimble JM and Guilak F: Mechanical signals as regulators of stem cell fate. Curr Top Dev Biol. 60:91–126. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Pillai AK, Andring B, Patel A, Trimmer C and Kalva SP: Portal hypertension: A review of portosystemic collateral pathways and endovascular interventions. Clin Radiol. 70:1047–1059. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Berzigotti A, Seijo S, Reverter E and Bosch J: Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol. 7:141–155. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Takabatake H, Matsueda K and Yamamoto H: Portal hypertension in patients with liver cirrhosis: Diagnostic accuracy of spleen stiffness. Radiology. 279:609–619. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Bloom S, Kemp W and Lubel J: Portal hypertension: Pathophysiology, diagnosis and management. Intern Med J. 45:16–26. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Ksiazyk J, Lyszkowska M and Kierkus J: Energy metabolism in portal hypertension in children. Nutrition. 12:469–474. 1996. View Article : Google Scholar : PubMed/NCBI

14 

Arias N, Méndez M, Arias J and Arias JL: Brain metabolism and spatial memory are affected by portal hypertension. Metab Brain Dis. 27:183–191. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Mohan P and Venkataraman J: Minimal hepatic encephalopathy in noncirrhotic portal hypertension. Eur J Gastroenterol Hepatol. 23:194–195. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Vogels BA, van Steynen B, Maas MA, Jörning GG and Chamuleau RA: The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy. J Hepatol. 26:387–395. 1997. View Article : Google Scholar : PubMed/NCBI

17 

Perisic M, Ilic-Mostic T, Stojkovic M, Culafic D and Sarenac R: Doppler hemodynamic study in portal hypertension and hepatic encephalopathy. Hepatogastroenterology. 52:156–160. 2005.PubMed/NCBI

18 

Petersen MC, Vatner DF and Shulman GI: Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 13:572–587. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Boden G, Cheung P, Stein TP, Kresge K and Mozzoli M: FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab. 283:E12–E19. 2002. View Article : Google Scholar : PubMed/NCBI

20 

Yang WM, Jeong HJ, Park SY and Lee W: Saturated fatty acid-induced miR-195 impairs insulin signaling and glycogen metabolism in HepG2 cells. FEBS Lett. 588:3939–3946. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, Xu HE, Shulman GI, Kliewer SA and Mangelsdorf DJ: FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science. 331:1621–1624. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Liu TY, Shi CX, Gao R, Sun HJ, Xiong XQ, Ding L, Chen Q, Li YH, Wang JJ, Kang YM and Zhu GQ: Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes. Clin Sci (Lond). 129:839–850. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Prats C, Graham TE and Shearer J: The dynamic life of the glycogen granule. J Biol Chem. 293:7089–7098. 2018. View Article : Google Scholar : PubMed/NCBI

24 

Watanabe S, Nagashio Y, Asaumi H, Nomiyama Y, Taguchi M, Tashiro M, Kihara Y, Nakamura H and Otsuki M: Pressure activates rat pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 287:G1175–G1181. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Wu HJ, Zhang ZQ, Yu B, Liu S, Qin KR and Zhu L: Pressure activates Src-dependent FAK-Akt and ERK1/2 signaling pathways in rat hepatic stellate cells. Cell Physiol Biochem. 26:273–280. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

27 

Fang W, Guo J, Cao Y, Wang S, Pang C, Li M, Dou L, Man Y, Huang X, Shen T and Li J: MicroRNA-20a-5p contributes to hepatic glycogen synthesis through targeting p63 to regulate p53 and PTEN expression. J Cell Mol Med. 20:1467–1480. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Isogai T, Park JS and Danuser G: Cell forces meet cell metabolism. Nat Cell Biol. 19:591–593. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Dziegala M, Kobak KA, Kasztura M, Bania J, Josiak K, Banasiak W, Ponikowski P and Jankowska EA: Iron depletion affects genes encoding mitochondrial electron transport chain and genes of non-oxidative metabolism, pyruvate kinase and lactate dehydrogenase, in primary human cardiac myocytes cultured upon mechanical stretch. Cells. 7(pii): E1752018. View Article : Google Scholar : PubMed/NCBI

30 

Yi SH, Zhang Y, Tang D and Zhu L: Mechanical force and tensile strain activated hepatic stellate cells and inhibited retinol metabolism. Biotechnol Lett. 37:1141–1152. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Denault AY, Beaubien-Souligny W, Elmi-Sarabi M, Eljaiek R, El-Hamamsy I, Lamarche Y, Chronopoulos A, Lambert J, Bouchard J and Desjardins G: Clinical significance of portal hypertension diagnosed with bedside ultrasound after cardiac surgery. Anesth Analg. 124:1109–1115. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Johnson TJ, Quigley EM, Adrian TE, Jin G and Rikkers LF: Glucagon, stress, and portal hypertension. Plasma glucagon levels and portal hypertension in relation to anesthesia and surgical stress. Dig Dis Sci. 40:1816–1823. 1995. View Article : Google Scholar : PubMed/NCBI

33 

Mohamed JS, Lopez MA and Boriek AM: Mechanical stretch up-regulates microRNA-26a and induces human airway smooth muscle hypertrophy by suppressing glycogen synthase kinase-3β. J Biol Chem. 285:29336–29347. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Ørtenblad N, Westerblad H and Nielsen J: Muscle glycogen stores and fatigue. J Physiol. 591:4405–4413. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Roach PJ, Depaoli-Roach AA, Hurley TD and Tagliabracci VS: Glycogen and its metabolism: Some new developments and old themes. Biochem J. 441:763–787. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Nakano K, Takeshita S, Kawasaki N, Miyanaga W, Okamatsu Y, Dohi M and Nakagawa T: AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice. Int J Mol Med. 39:841–850. 2017. View Article : Google Scholar : PubMed/NCBI

37 

Han C, Wei S, He F, Liu D, Wan H, Liu H, Li L, Xu H, Du X and Xu F: The regulation of lipid deposition by insulin in goose liver cells is mediated by the PI3K-AKT-mTOR signaling pathway. PLoS One. 10:e00987592015. View Article : Google Scholar : PubMed/NCBI

38 

Nocito L, Kleckner AS, Yoo EJ, Jones Iv AR, Liesa M and Corkey BE: The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes. PLoS One. 10:e01228182015. View Article : Google Scholar : PubMed/NCBI

39 

Chang YS, Tsai CT, Huangfu CA, Huang WY, Lei HY, Lin CF, Su IJ, Chang WT, Wu PH, Chen YT, et al: ACSL3 and GSK-3β are essential for lipid upregulation induced by endoplasmic reticulum stress in liver cells. J Cell Biochem. 112:881–893. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Venna VR, Benashski SE, Chauhan A and McCullough LD: Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: The role of TAK1. Learn Mem. 22:336–343. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Hientz K, Mohr A, Bhakta-Guha D and Efferth T: The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget. 8:8921–8946. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M and Yang X: p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 13:310–316. 2011. View Article : Google Scholar : PubMed/NCBI

43 

Liu J, Zhang C, Hu W and Feng Z: Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett. 356:197–203. 2015. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Shen, J., Sun, Y., Shen, S., Luo, X., Chen, J., & Zhu, L. (2019). Pressure suppresses hepatocellular glycogen synthesis through activating the p53/Pten pathway. Molecular Medicine Reports, 19, 5105-5114. https://doi.org/10.3892/mmr.2019.10177
MLA
Shen, J., Sun, Y., Shen, S., Luo, X., Chen, J., Zhu, L."Pressure suppresses hepatocellular glycogen synthesis through activating the p53/Pten pathway". Molecular Medicine Reports 19.6 (2019): 5105-5114.
Chicago
Shen, J., Sun, Y., Shen, S., Luo, X., Chen, J., Zhu, L."Pressure suppresses hepatocellular glycogen synthesis through activating the p53/Pten pathway". Molecular Medicine Reports 19, no. 6 (2019): 5105-5114. https://doi.org/10.3892/mmr.2019.10177