Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor Levels in Pathogenesis of Non-Alcoholic Fatty Liver

Authors

  • Fadhil Jawad Al-Tu’ma Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Kerbala,Iraq.
  • Ibtihal Hameed Gazi Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala,Kerbala, Iraq
  • Atheer Hameid Odda Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Kerbala,Iraq.
  • Jawad Fadhil Al-Tu’ma Department of Internal Medicine, Al-Zahraa Teaching Hospital, Al-Hussein Medical City, Kerbala Health Directorates,Kerbala, Iraq.

DOI:

https://doi.org/10.22317/imj.v7i3.1252

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is one of the main causes of cirrhosis and hepatocellular carcinoma. Recently, the stress response protein mesencephalon-astrocyte-derived neurotrophic factor (MANF) has been shown to regulate hepatic and systemic metabolic homeostasis.

Objectives: The main purpose of this study is to investigate the relationship between mesencephalon-astrocyte-derived neurotrophic factor levels with other anthropometric indicators, and its function in the pathogenesis of non-alcoholic fatty liver disease.

Materials and Methods: A total of 120 patients with ages ranging between 40 to 73 years were included in this study and their serum samples were collected and kept at -2 °C. The liver function test, lipid profile, and albumin were determined using the automated biochemistry analyzer, while the mesencephalic astrocyte-derived neurotrophic factor biomarker was determined by the ELIZA technique.

Results: Our study showed that MANF levels decrease with age, and decreased MANF levels are associated with inflammatory phenotypes. The mean levels of ALT, ALP, AST, TSB, and the ALT/AST ratio in the non-alcoholic fatty liver patients were significantly higher than that for the non-fatty liver patients. As well, the mean level of MANF in the non-fatty liver patients was 305.25 ± 110.49 mg/dl which was significantly higher in the non-alcoholic fatty liver group (157.52). (p ≤ 0.001)

Conclusion: A novel finding of our study is that the reduction of serum MANF levels is strongly associated with the pathogenesis of non-alcoholic fatty liver disorders and could be used as a potential therapeutic target in the treatment of hepatic disorders.

References

Cotter, T. G. and Rinella, M. (2020). Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology, 158(7) : 1851-1864.‏

Nasiri-Ansari, N., Androutsakos, T., Flessa, C. M., Kyrou, I., Siasos, G., Randeva, H. S. and Papavassiliou, A. G. (2022). Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells, 11(16), 2511..

Day, C. P., and James, O. F. (1998). Steatohepatitis: a tale of two “hits”?. Gastroenterology, 114(4) : 842-845.‏

Buzzetti, E., Pinzani, M. and Tsochatzis, E. A. (2016). The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism, 65(8) : 1038-1048.‏

Marchesini, G., Brizi, M., Morselli-Labate, A. M., Bianchi, G., Bugianesi, E., McCullough, A. J., and Melchionda, N. (1999). Association of nonalcoholic fatty liver disease with insulin resistance. The American Journal of medicine, 107(5) : 450-455.‏

Wu, H., Li, H., Wen, W., Wang, Y., Xu, H., Xu, M., ... & Luo, J. (2021). MANF protects pancreatic acinar cells against alcohol‐induced endoplasmic reticulum stress and cellular injury. Journal of Hepato‐Biliary‐Pancreatic Sciences, 28(10), 883-892.‏

Tseng, K. Y., Danilova, T., Domanskyi, A., Saarma, M., Lindahl, M., & Airavaara, M. (2017). MANF is essential for neurite extension and neuronal migration in the developing cortex. eneuro, 4(5).‏

Sousa-Victor, P., Neves, J., Cedron-Craft, W., Ventura, P. B., Liao, C. Y., Riley, R. R. and Jasper, H. (2019). MANF regulates metabolic and immune homeostasis in aging and protects against liver damage. Nature Metabolism, 1(2) : 276-290.‏

Mizobuchi, N., Hoseki, J., Kubota, H., Toyokuni, S., Nozaki, J. I., Naitoh, M., ... and Nagata, K. (2007). ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Cell structure and function, 32(1) : 41-50.‏

Hellman, M., Arumäe, U., Yu, L. Y., Lindholm, P., Peränen, J., Saarma, M. and Permi, P. (2011). Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. Journal of biological chemistry, 286(4) : 2675-2680.‏

Kim, Y., Park, S. J. andChen, Y. M. (2017). Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles. Translational Research, 188 : 1-9.‏

Wu, T., Liu, Q., Li, Y., Li, H., Chen, L., Yang, X. and He, J. (2021). Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway. Journal of Experimental Medicine, 218(6) : e20201203.‏

Eslam, M., Newsome, P. N., Sarin, S. K., Anstee, Q. M., Targher, G., Romero-Gomez, M. and George, J. (2020). A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of hepatology, 73(1) : 202-209.‏

Sousa-Victor, P., Neves, J., Cedron-Craft, W., Ventura, P. B., Liao, C. Y., Riley, R. R. and Jasper, H. (2019). MANF regulates metabolic and immune homeostasis in aging and protects against liver damage. Nature Metabolism, 1(2) : 276-290.‏

He, M., Wang, C., Long, X. H., Peng, J. J., Liu, D. F., Yang, G. Y. and Zhang, L. L. (2020). Mesencephalic astrocyte-derived neurotrophic factor ameliorates steatosis in HepG2 cells by regulating hepatic lipid metabolism. World journal of gastroenterology, 26(10) : 1029.‏

Cordero-Llana, Ó., Houghton, B. C., Rinaldi, F., Taylor, H., Yáñez-Muñoz, R. J., Uney, J. B. and Caldwell, M. A. (2015). Enhanced efficacy of the CDNF/MANF family by combined intranigral overexpression in the 6-OHDA rat model of Parkinson's disease. Molecular Therapy, 23(2) : 244-254.‏.

Ezhilarasan D, Lakshmi T. 2022 A Molecular Insight into the Role of Antioxidants in Nonalcoholic Fatty Liver Diseases. Oxid Med Cell Longev. 2022 May 11: 9233650.

‏ Yang, L., Shen, W. W., Shao, W., Zhao, Q., Pang, G. Z., Yang, Y. and Shen, Y. X. (2023). MANF ameliorates DSS-induced mouse colitis via restricting Ly6ChiCX3CR1int macrophage transformation and suppressing CHOP-BATF2 signaling pathway. Acta Pharmacologica Sinica : 1-16.

‏Donini, L. M., Pinto, A., Giusti, A. M., Lenzi, A. and Poggiogalle, E. (2020). Obesity or BMI paradox? Beneath the tip of the iceberg. Frontiers in Nutrition, 7 : 53.

Schindhelm, R. K., Diamant, M., Dekker, J. M., Tushuizen, M. E., Teerlink, T., & Heine, R. J. (2006). Alanine aminotransferase as a marker of non‐alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes/metabolism research and reviews, 22(6) : 437-443.‏

Su, W., Mao, Z., Liu, Y., Zhang, X., Zhang, W., Gustafsson, J. A. and Guan, Y. (2019). Role of HSD17B13 in the liver physiology and pathophysiology. Molecular and cellular endocrinology, 489 : 119-125.‏

Chen, C. B., Hammo, B., Barry, J., & Radhakrishnan, K. (2021). Overview of albumin physiology and its role in pediatric diseases. Current gastroenterology reports, 23(8) : 11.‏

Sousa-Victor, P., Neves, J., Cedron-Craft, W., Ventura, P. B., Liao, C. Y., Riley, R. R. and Jasper, H. (2019). MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage. Nature metabolism, 1(2) : 276-290.

‏Yang S., Huang S., Gaertig M. A., Li X. J., Li S. (2014). Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice. Neuron, 81: 349–365.

Wu, T., Liu, Q., Li, Y., Li, H., Chen, L., Yang, X. and He, J. (2021). Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway. Journal of Experimental Medicine, 218(6) : e20201203.‏

Tang Q, Li Y, He J. MANF: an emerging therapeutic target for metabolic diseases. Trends Endocrinol Metab. 2022 Apr;33(4):236-246. doi: 10.1016/j.tem.2022.01.001. Epub 2022 Feb 5. PMID: 35135706.

Galli, E., Rossi, J., Neumann, T., Andressoo, J. O., Drinda, S. and Lindholm, P. (2019). Mesencephalic astrocyte-derived neurotrophic factor is upregulated with therapeutic fasting in humans and diet fat withdrawal in obese mice. Scientific reports, 9(1) : 14318.‏

Adams, L. A., Angulo, P. and Lindor, K. D. (2005). Nonalcoholic fatty liver disease. Cmaj, 172(7) : 899-905.‏

Xu, K., Zheng, P., Zhao, S., Wang, M., Tu, D., Wei, Q. and Xie, P. (2022). MANF/EWSR1/ANXA6 pathway might as the bridge between hypolipidemia and major depressive disorder. Translational Psychiatry, 12(1), 527.‏

He, M., Wang, C., Long, X. H., Peng, J. J., Liu, D. F., Yang, G. Y. and Zhang, L. L. (2020). Mesencephalic astrocyte-derived neurotrophic factor ameliorates steatosis in HepG2 cells by regulating hepatic lipid metabolism. World journal of gastroenterology, 26(10) : 1029.‏

Published

2023-10-29

How to Cite

Jawad Al-Tu’ma, F. ., Hameed Gazi, I. ., Hameid Odda, A. ., & Fadhil Al-Tu’ma, J. . (2023). Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor Levels in Pathogenesis of Non-Alcoholic Fatty Liver . Iraq Medical Journal, 7(3). https://doi.org/10.22317/imj.v7i3.1252

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