Mechanism of growth differentiation factor 11 regulating nonalcoholic fatty liver disease

Tao ZHANG; Xuecui YIN; Feifei REN; Lin DONG; Jia ZHANG; Gaofeng LU

doi:10.3969/j.issn.1001-5256.2023.09.011

Volume 39 Issue 9

Sep. 2023

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Article Navigation > Journal of Clinical Hepatology > 2023 > 39(9): 2103-2109

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Mechanism of growth differentiation factor 11 regulating nonalcoholic fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2023.09.011

Department of Gastroenterology，The Second Affiliated Hospital of Zhengzhou University，Zhengzhou 450014，China

Research funding:

Basic and Frontier Technology Research Program of Henan Province (162300410128);

Top Talent Program of Science and Technology Innovation Talent Cultivation Fund (2020BJRCB01)

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Corresponding author: LU Gaofeng， lugaofeng78@163.com （ORCID： 0000－0002－1771－3167）
Received Date: 2023-01-15
Accepted Date: 2023-02-15
Published Date: 2023-09-19

Abstract

Abstract

Objective To investigate the effect of growth differentiation factor 11 （GDF11） on free fatty acid （FFA）－induced hepatocyte steatosis and the role of autophagy in this process. Methods A model of nonalcoholic fatty liver disease was established invitro， and recombinant GDF11 was added to observe its effect on hepatocyte steatosis and apoptosis. Chloroquine was added to inhibit autophagy， and the change in hepatocyte autophagy flow induced by GDF11 and its association with steatosis were explored. AM－12 cells were divided into control group， control＋GDF11 group， model group， GDF11 group， and GDF11＋chloroquine group. The cells in the control group were cultured with DMEM complete culture medium； the cells in the control＋GDF11 group were cultured with GDF11 （100 ng/mL） added to the complete culture medium； the cells in the model group were treated with 1 mmol/L FFA （with an oleic acid/palmitic acid ratio of 2∶1） to induce hepatocyte steatosis； the cells in the GDF11 group were co－cultured with FFA and GDF11； the cells in the GDF11＋chloroquine group were co-cultured with FFA， GDF11， and 20 μmol/L chloroquine （an autophagy inhibitor）. Lipid droplet fluorescence staining and an automatic biochemical analyzer were used to observe lipid deposition in hepatocytes； Western blotting and protein immunofluorescence assay were used to measure the levels of autophagy－related proteins （p62 and LC3B） and the level of autophagy； JC－1 staining was used to measure mitochondrial membrane potential. A one－way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t－test was used for further comparison between two groups. Results Compared with the model group， the GDF11 group and the control group had significant reductions in the accumulation and volume of lipid droplets in hepatocytes （all P<0.05）. The model group had a significantly higher level of triglyceride in hepatocytes than the GDF11 group and the control group （P<0.000 1）. Compared with the control group， the model group had a significantly lower level of LC3B （P<0.05） and a significantly higher level of p62 （P<0.05）； compared with the GDF11 group， the GDF11＋chloroquine group had a significant increase in the level of triglyceride in hepatocytes （P<0.001）； compared with the model group， the GDF11 group had a significant reduction in the content of ROS （P<0.05）. After FFA induction， there was a significant increase in green fluorescence in cytoplasma， and compared with the control group， the model group had a significant increase in JC－1 monomers/aggregates （P<0.000 1） and a reduction in mitochondrial membrane potential； there was a reduction in the intensity of green fluorescence after the addition of GDF11， and compared with the model group， the GDF11 group had a significant reduction in JC－1 monomers/aggregates （P<0.05） and an increase in mitochondrial membrane potential. Conclusion GDF11 can alleviate FFA－induced lipotoxic liver injury and improve hepatocyte steatosis in nonalcoholic fatty liver disease by promoting autophagy.
- Non－alcoholic Fatty Liver Disease,
- Growth Differentiation Factor 11,
- Autophagy

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References

[1]	POWELL EE, WONG VWS, RINELLA M. Non－alcoholic fatty liver disease[J]. Lancet, 2021, 397( 10290): 2212－ 2224. DOI: 10.1016/S0140－6736(20)32511－3.
[2]	RUISSEN MM, MAK AL, BEUERS U, et al. Non－alcoholic fatty liver disease: A multidisciplinary approach towards a cardiometabolic liver disease[J]. Eur J Endocrinol, 2020, 183( 3): R57－R73. DOI: 10.1530/EJE－20－0065.
[3]	TANAKA N, KIMURA T, FUJIMORI N, et al. Current status, problems, and perspectives of non－alcoholic fatty liver disease research[J]. World J Gastroenterol, 2019, 25( 2): 163－ 177. DOI: 10.3748/wjg.v25.i2.163.
[4]	LOOMBA R, FRIEDMAN SL, SHULMAN GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease[J]. Cell, 2021, 184( 10): 2537－ 2564. DOI: 10.1016/j.cell.2021.04.015.
[5]	GLUCHOWSKI NL, BECUWE M, WALTHER TC, et al. Lipid droplets and liver disease: From basic biology to clinical implications[J]. Nat Rev Gastroenterol Hepatol, 2017, 14( 6): 343－ 355. DOI: 10.1038/nrgastro.2017.32.
[6]	KRAHMER N, FARESE RV Jr, WALTHER TC. Balancing the fat: Lipid droplets and human disease[J]. EMBO Mol Med, 2013, 5( 7): 973－ 983. DOI: 10.1002/emmm.201100671.
[7]	MORTEZAEE K, KHANLARKHANI N. Melatonin application in targeting oxidative－induced liver injuries: A review[J]. J Cell Physiol, 2018, 233( 5): 4015－ 4032. DOI: 10.1002/jcp.26209.
[8]	LINHART KB, GLASSEN K, PECCERELLA T, et al. The generation of carcinogenic etheno－DNA adducts in the liver of patients with nonalcoholic fatty liver disease[J]. Hepatobiliary Surg Nutr, 2015, 4( 2): 117－ 123. DOI: 10.3978/j.issn.2304－3881.2015.01.14.
[9]	LIU Q, BENGMARK S, QU S. The role of hepatic fat accumulation in pathogenesis of non－alcoholic fatty liver disease(NAFLD)[J]. Lipds Heath Dis, 2010, 9( 1): 1－ 9. DOI: 10.1186/1476－511X－9－42.
[10]	WOBSER H, DORN C, WEISS TS, et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells[J]. Cell Res, 2009, 19( 8): 996－ 1005. DOI: 10.1038/cr.2009.73.
[11]	BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68( 6): 394－ 424. DOI: 10.3322/caac.21492.
[12]	WALKER RG, POGGIOLI T, KATSIMPARDI L, et al. Biochemistry and biology of GDF11 and myostatin: Similarities, differences, and questions for future investigation[J]. Circ Res, 2016, 118( 7): 1125－ 1141. DOI: 10.1161/CIRCRESAHA.116.308391.
[13]	LU BX, ZHONG JN, PAN JF, et al. Gdf11 gene transfer prevents high fat diet－induced obesity and improves metabolic homeostasis in obese and STZ－induced diabetic mice[J]. J Transl Med, 2019, 17( 1): 422. DOI: 10.1186/s12967－019－02166－1.
[14]	FROHLICH J, KOVACOVICOVA K, MAZZA T, et al. GDF11 induces mild hepatic fibrosis independent of metabolic health[J]. Aging, 2020, 12( 20): 20024－ 20046. DOI: 10.18632/aging.104182.
[15]	ZHOU J, PANG J, TRIPATHI M, et al. Spermidine－mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non－alcoholic steatohepatitis progression[J]. Nat Commun, 2022, 13( 1): 5202. DOI: 10.1038/s41467－022－32788－x.
[16]	GADIPARTHI C, SPATZ M, GREENBERG S, et al. NAFLD epidemiology, emerging pharmacotherapy, liver transplantation implications and the trends in the United States[J]. J Clin Transl Hepatol, 2020, 8( 2): 215－ 221. DOI: 10.14218/JCTH.2020.00014.
[17]	BYRNES K, BLESSINGER S, BAILEY NT, et al. Therapeutic regulation of autophagy in hepatic metabolism[J]. Acta Pharm Sin B, 2022, 12( 1): 33－ 49. DOI: 10.1016/j.apsb.2021.07.021.
[18]	ZHONG CC, ZHAO T, HOGSTRAND C, et al. Copper(Cu) induced changes of lipid metabolism through oxidative stress－mediated autophagy and Nrf2/PPARγ pathways[J]. J Nutr Biochem, 2022, 100: 108883. DOI: 10.1016/j.jnutbio.2021.108883.
[19]	SCORLETTI E, CARR RM. A new perspective on NAFLD: Focusing on lipid droplets[J]. J Hepatol, 2022, 76( 4): 934－ 945. DOI: 10.1016/j.jhep.2021.11.009.
[20]	LIN CW, ZHANG H, LI M, et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non－alcoholic fatty liver conditions in mice[J]. J Hepatol, 2013, 58( 5): 993－ 999. DOI: 10.1016/j.jhep.2013.01.011.
[21]	DAI Z, SONG GQ, BALAKRISHNAN A, et al. Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells[J]. Gut, 2020, 69( 6): 1104－ 1115. DOI: 10.1136/gutjnl－2019－318812.
[22]	JIAO L, SHAO YC, YU Q, et al. GDF11 replenishment protects against hypoxia－mediated apoptosis in cardiomyocytes by regulating autophagy[J]. Eur J Pharmacol, 2020, 885: 173495. DOI: 10.1016/j.ejphar.2020.173495.

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Mechanism of growth differentiation factor 11 regulating nonalcoholic fatty liver disease

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