Specificities of lipotoxicity of free fatty acids and cytokine profile in patients with chronic diffuse liver diseases

  • V. I. Didenko Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine
  • I. A. Klenina Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine
  • О. M. Tatarchuk Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine
  • O. I. Hrabovska Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine
  • O. P. Petishko Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine
Keywords: alcoholic liver disease; toxic hepatitis; non-alcoholic fatty liver disease; saturated free fatty acids; unsaturated free fatty acids; interleukin.


Non-alcoholic fatty liver disease is an important cause of global liver disease characterized by diffuse hepatocytes with hepatocellular ballooning, intrahepatic inflammation and progressive fibrosis. A relevant task is the study of the relationship between content of free fatty acids and serum cytokine profile in patients with chronic diffuse liver diseases. A total of 74 people with chronic diffuse liver diseases were examined, including 32 patients with non-alcoholic fatty liver disease, 22 patients with alcoholic liver disease, 20 patients with toxic hepatitis. Chromatographic examination of free fatty acids (FFA) in blood serum was carried out using a Chromatek-Crystal 5000 gas chromatography system. Patients with chronic diffuse liver diseases had a significant increase in the level of unsaturated free fatty acids (USFA) in cases of toxic hepatitis (by 2.92 times, P > 0.05) and a decrease in the level of saturated free fatty acids (SFA) in cases of non-alcoholic fatty liver disease (by 1.52 times, P > 0.05) compared with the control group; the balance between omega-6 and omega-3 PUFA significantly changed due to increase in linoleic acid in patients with alcoholic liver disease and toxic hepatitis (by 1.91 and 2.11 times, respectively) and arachidonic acid in patients with toxic hepatitis (by 1.78 times). The level of interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-α) were determined. In patients suffering chronic diffuse liver diseases there were multidirectional changes in the composition of free fatty acids of blood serum: a significant increase in the level of USFA, levels ІL-6 in toxic hepatitis; a decrease in the level of SFA, levels ІL-6 and TNF-α during non-alcoholic fatty liver disease; increased TNF-α production, ІL-6 during alcoholic liver disease compared with the control group. Significant change occurred in the balance between omega-6 and omega-3 PUFA due to increase in linoleic acid in cases of alcoholic liver disease and toxic hepatitis and arachidonic acid in cases of toxic hepatitis. The revealed correlations support the hypothesis that inflammation and lipotoxicity of FFA of blood serum contribute to the development and progression of structural changes in the liver. However, the pathomechanism of lipid metabolism and cytokine regulation with different etiological factors have their own characteristics, which should be taken into account when treating patients of these groups. Prospects for further research: these parameters may be used for serologic biomarkers of liver disease and development and implementation of the ratio between FFA and cytokines for the differential diagnosis of chronic diffuse liver disease in medical practice.


Aitbaev, K. A., Murkamilov, I. T., & Fomin, V. V. (2017). Bolezni pecheni: Patogenet-icheskaia rol’ kishechnogo mikrobioma i potentsial terapii po ego moduliatsii [Liv-er diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation]. Terapevticheskii Arkhiv, 89(8), 120–128 (in Russian).

Akazawa, Y., Cazanave, S., Mott, J. L., Elmi, N., Bronk, S. F., Kohno, S., Charlton, M. R., & Gores, G. J. (2010). Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. Journal of Hepatology, 52(4), 586–593.

Alves-Bezerra, M., & Cohen, D. E. (2017). Triglyceride metabolism in the liver. Com-prehensive Physiology, 8(1), 1–8.

Bedossa, P. (2017). Pathology of non-alcoholic fatty liver disease. Liver International, 37(1), 85–89.

Bellanti, F., Villani, R., Tamborra, R., Blonda, M., Iannelli, G., di Bello, G., Facciorusso, A., Poli, G., Iuliano, L., Avolio, C., Vendemiale, G., & Serviddio, G. (2018). Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression. Redox Biology, 15, 86–96.

Boutari, C., Perakakis, N., & Mantzoros, C. S. (2018). Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinology and Metabolism, 33(1), 33–43.

Caballería, L., Pera, G., Arteaga, I., Rodríguez, L., Alumà, A., Morillas, R. M., de la Ossa, N., Díaz, A., Expósito, C., Miranda, D., Sánchez, C., Prats, R. M., Urquizu, M., Sal-gado, A., Alemany, M., Martinez, A., Majeed, I., Fabrellas, N., Graupera, I., Planas, R., Ojanguren, I., Serra, M., Torán, P., Caballería, J., & Ginès, P. (2018). High preva-lence of liver fibrosis among European adults with unknown liver disease: A popu-lation-based study. Clinical Gastroenterology and Hepatology, 16(7), 1138–1145.

Chen, R., Han, S., Dong, D., Wang, Y., Liu, Q., Xie, W., Li, M., & Yao, M. (2015). Serum fatty acid profiles and potential biomarkers of ankylosing spondylitis determined by gas chromatography-mass spectrometry and multivariate statistical analysis. Biomedical Chromatography, 29(4), 604–611.

Copaci, I., Lupescu, I., Caceaune, E., Chiriac, G., & Ismail, G. (2015). Noninvasive markers of improvement of liver steatosis achieved by weight reduction in patients with nonalcoholic fatty liver disease. Romanian Journal of Internal Medicine, 53(1), 54–62.

Di Ciaula, A., Passarella, S., Shanmugam, H., Noviello, M., Bonfrate, L., Wang, D. Q.-H., & Portincasa, P. (2021). Nonalcoholic fatty liver disease (NAFLD). Mitochondria as players and targets of therapies?. International Journal of Molecular Sciences, 22(10), 5375.

Didenko, V. I., Klenina, I. A., Tatarchuk, O. M., & Petishko, O. P. (2019). Diahnostychni markery prohresuvannia fibroznykh zmin pechinky u patsiientiv iz khronich-nymy dyfuznymy zakhvoriuvanniamy pechinky alkoholnoho henezu [Correla-tion of immunological and biochemical indicators in patients with chronic diffuse liver diseases depending on the etiological factors of steatosis and liver fibrosis]. Gastroenterology, 53(2), 115–122 (in Ukrainian).

Didenko, V. I., Klenina, I. A., Babii, S. O., & Karachynova, V. A. (2017). Aktualnist’ vyznachennia spektra zhyrnykh kyslot u biolohichnykh substratakh u diahnosty-tsi hastroenterolohichnykh zakhvoriuvan [Topicality of identification of free fatty acids pattern in biologic substrates in the diagnosis of gastroenterological diseases]. Gastroenterology, 51(2), 137–141 (in Ukrainian).

European Association for the Study of the Live (2019). EASL clinical practice guide-lines: Drug‐induced liver injury. Journal of Hepatology, 70, 1222–1261.

Engin, A. (2017). Non-alcoholic fatty liver disease. Advances in Experimental Medicine and Biology, 960, 443–467.

Fadeenko, G. D., Kushnir, I. E., Mozhina, T. L., Chernova, V. M., & Solomentseva, T. A. (2019). Rol syrovatkovykh biomarkeriv u diahnostytsi nealkoholnoi zhyrovoji khvoroby pechinky [The role of serum biomarkers in the diagnosis of nonalcohol-ic fatty liver disease]. Modern Gastroenterology, 107, 58–65 (in Russian).

Fang, Y. L., Chen, H., Wang, C. L., & Liang, L. (2018). Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”. World Journal of Gastroenterology, 24(27), 2974–2983.

Goldberg, D., Dita, I. C., Saeian, K., Lalehzari, M., Aronsohn, A., Gorospe, E. C., & Charl-ton, M. (2017). Changes in the prevalence of hepatitis C virus infection, nonalco-holic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liv-er failure on the waitlist for liver trans-plantation. Gastroenterology, 152(5), 1090–1099.

Gubergrits, N. B., Byelyayeva, N. V., Berezhna, E. V., Klochkov, A. Y., Fomenko, P. G., & Tsys, A. V. (2019). Kyshkova mikrobiota pry zakhvoriuvanniakh pechinky: Suchasnyi stan problem [Intestinal microbiota in liver diseases: Current state of the problem]. Modern Gastroenterology, 107, 79–89 (in Russian).

Hastings, K. L., Green, M. D., Gao, B., Ganey, P. E., Roth, R. A., & Burleson, G. R. (2020). Beyond metabolism: Role of the immune system in hepatic toxicity. In-ternational Journal of Toxicology, 39(2), 151–164.

Ibrahim, E. A., Moawed, F. S., & Moustafa, E. M. (2020). Suppression of inflammatory cascades via novel cinnamic acid nanoparticles in acute hepatitis rat model. Ar-chives of Biochemistry and Biophysics, 15(696), 108658.

Lazebnik, L. B., Radchenko, V. G., Dzhadhav, S. N., Sitkin, S. I., & Seliverstov, P. V. (2019). Systemic inflammation and non-alcoholic fatty liver disease. Clinical and Experimental Gastroenterology, 165(5), 29–41.

Maiuri, A. R., Wassink, B., Turkus, J. D., Breier, A. B., Lansdell, T., Kaur, G., Hession, S. L., Ganey, P. E., & Roth, R. A. (2017). Synergistic cytotoxicity from drugs and cy-tokines in vitro as an approach to classify drugs according to their potential to cause idiosyncratic hepatotoxicity: a proof-of-concept study. Journal of Pharma-cology and Experimental Therapeutics, 362(3), 459–473.

Mannaa, F. A., & Abdel-Wahhab, K. G. (2016). Physiological potential of cytokines and liver damages. Hepatoma Research, 2, 131–143.

Niederreiter, L., & Til, H. (2018). Cytokines and fatty liver diseases. Liver Research, 2(1), 14–20.

Perez-Cornago, A., Brennan, L., Ibero-Baraibar, I., Hermsdorff, H. H. M., O’Gorman, A., Mzulet, A., & Martínez, J. А. (2014). Metabolomics identifies changes in fatty acid and amino acid profiles in serum of overweight older adults following a weight loss intervention. Journal of Physiology and Biochemistry, 70(2), 593–602.

Raza, S., Rajak, S., Anjum, B., & Sinha, R. A. (2019). Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma. Hepatoma, 5, 42.

Reccia, I., Kumar, J., Akladios, C., Virdis, F., Pai, M., Habib, N., & Spalding, D. (2017). Non-alcoholic fatty liver disease: A sign of systemic disease. Metabolism, 72, 94–108.

Sandhu, N., & Navarro, V. (2020). Drug‐induced liver injury in gi practice. Hepatology Communications, 4(5), 631–645.

Sanyal, A. J. (2019). Past, present and future perspectives in nonalcoholic fatty liver disease. Nature Reviews Gastroenterology and Hepatology, 16(6), 377–386.

Stepanov, Y. M., Didenko, V. I., Klenina, I. A., Karachinova, V. A., & Oshmianska, N. Y. (2018). Spektr zhirnyh kislot syvorotki krovi u bol’nyh hronicheskim diffuz-nym zabolevaniem pecheni v zavisimosti ot etiologii i morfologicheskih osoben-nostej [Spectrum of serum fatty acids in patients with chronic diffuse liver disease depending on etiology and morphological features]. Gastroenterology, 52(3), 23–30 (in Ukrainian).

Svegliati-Baroni, G., Pierantonelli, I., Torquato, P., Marinelli, R., Ferreri, C., Chatgilialoglu, C., Bartolini, D., & Galli, F. (2019). Lipidomic biomarkers and mechanisms of lipo-toxicity in non-alcoholic fatty liver disease. Free Radical Biology and Medicine, 20(144), 293–309.

Tatarchuk, O. M., Didenko, V. I., Melanich, S. L., & Kudryavtseva, V. Y. (2018). Imunolohichna reaktyvnistu khvorykh na khronichni dyfuzni zakhvoriuvannia pechinky [Immunological reactivity in patients with chronic diffuse liver diseases]. Gastroenterology, 52(4), 222–226 (in Ukrainian).

Woods, A., Williams, J. R., Muckett, P. J., Mayer, F. V., Liljevald, M., Bohloolyy, M., & Carling, D. (2017). Liver-specific activation of AMPK prevents steatosis on a high-fructose diet Cell Reports, 18(13), 3043–3051.

Younossi, Z. M. (2018). The epidemiology of nonalcoholic steatohepatitis. Clinical Liver Disease (Hoboken), 11(4), 92–94.

Younossi, Z. M., Anstee, Q. M., Marietti, M., Hardy, T., Henry, L., Eslam, M., George, J., & Bugianesi, E. (2018). Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nature Reviews Gastroenterology and Hepatology, 15(1), 11–20.

Zavhorodnia, N. Y., Lukianenko, O. Y., Klenina, I. A., Hrabovska, O. I., Tatarchuk, O. M., & Vishnarevska, N. S. (2020). Assessment of the intestinal microbiota and fe-cal shortchain fatty acids content in children with nonalcoholicfatty liver disease. Gastroenterology, 54(1), 56–62.

Zhang, M., Sun, W., Zhou, M., & Tang, Y. (2017). MicroRNA-27a regulates hepatic lipid metabolism and alleviates NAFLD via repressing FAS and SCD1. Scientific Reports, 7, 14493.

How to Cite
Didenko, V. I., Klenina, I. A., TatarchukО. M., Hrabovska, O. I., & Petishko, O. P. (2021). Specificities of lipotoxicity of free fatty acids and cytokine profile in patients with chronic diffuse liver diseases . Regulatory Mechanisms in Biosystems, 13(1), 3-9. https://doi.org/10.15421/022201