Histologic, Metabolic, and Inflammatory Changes in the Liver of High-fat Diet-induced Obese Rats before and after Vitamin D Administration
improved liver inflammation and injury by vitamin D
The current study aimed to investigate the effects of vitamin D administration on the markers of inflammation and metabolic damages in the liver of high-fat diet-induced obese rats. Forty male Wistar rats were divided into two groups of control receiving a normal diet (ND) and intervention receiving a high-fat diet (HFD). After 16 weeks, each group was divided into two groups including ND, ND + vitamin D, HFD, and HFD + vitamin D. Vitamin D was administered by oral gavage for five weeks at the dose of 500 IU/kg. Hepatic MCP-1, TGF-β, and NF-κB levels, serum liver enzymes, and serum lipids, and histological and structural changes in the liver were determined. Vitamin D administration significantly reduced the monocyte chemoattractant protein (MCP)-1 concentrations in the HFD + vitamin D group compared with the HFD group and reduced liver Transforming growth factor beta (TGF-β) levels in both vitamin D-treated groups (p<0.05). Moreover, a significant reduction in the serum levels of aspartate amino transferase (AST) and alanine amino transferase (ALT) in vitamin D treated groups was identified (p<0.05). A significant improvement in lipids and a pronounced improvement in the markers of liver histology damage including fat accumulation, aggregation of inflammatory cells, pre-apoptotic changes, hepatic sinusoidal dilatation, and necrotic pyknosis in the Kupffer cells were also identified. Our results demonstrated that vitamin D has potential effects in ameliorating the inflammatory, metabolic, and histologic changes in the liver of these animals.
2. Ramos EJ, Xu Y, Romanova I. Is obesity an inflamatuar disease? Surgery 2003; 134(2):329-35.
3. Hajiluian Gh, Abbasalizad-Farhangi M, Nameni G, Shahabi P, Megari-Abbasi M. Oxidative stress-induced cognitive impairment in obesity can be reversed by vitamin D administration inrats. Nutr Neurosci 2018; 21(10):744-752.
4. Schuster N, Krieglstein K. Mechanisms of TGF-beta-mediated apoptosis. Cell Tissue Res 2002; 307(1):1-14.
5. Karlmark RK, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr 1 monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 12: 261-74.
6. Tsuruta S, Nakamuta M, Enjoji M, Kotoh K, Hiasa K, Egashira K, et al. Anti-monocyte chemoattractant protein-1 gene therapy prevents dimethylnitrosamine-induced hepatic fibrosis in rats. Int J Mol Med 2004; 14(5):837-42.
7. Elsharkawy AM, Mann DA. Nuclear Factor-B and the hepatic inflammation-fibrosis-cancer axis. Hepatology 2007; 46(2):590-7.
8. Sunami Y, Leithauser F, Gul S, Fiedler K, Guldiken N, Espenlaub S, et al. Hepatic activation of IKK/NFjB signaling induces liver fibrosis via macrophage-mediated chronic inflammation. Hepatology 2012; 56(3):1117-28.
9. Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8(2):108-18.
10. Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr 2015; 55(9):1193-205.
11. Kitson MT, Roberts SK. Delivering the message: The importance of vitamin D status in chronic liver disease. J Hepatol 2012; 57(4):897–909.
12. Konstantakis C, Tselekouni P, Kalafateli M, Triantos C. Vitamin D deficiency in patients with liver cirrhosis. Ann Gastroenterol 2016; 29(3):297–306.
13. Skaaby T, Husemoen LL, Borglykke A, Jørgensen T, Thuesen BH, Pisinger C, et al. Vitamin D status, liver enzymes, and incident liver disease and mortality: a general population study. Endocrine 2014; 47(1):213-20.
14. Chung GE, Kim D, Kwak MS, Yang JI, Yim JY, Lim SH, et al. The serum vitamin D level is inversely correlated with nonalcoholic fatty liver disease. Clin Mol Hepatol 2016; 22(1):146–51.
15. Hajiluian G, Nameni G, Shahabi P, Mesgari-Abbasi M, Sadigh-Eteghad S, Farhangi MA. Vitamin D administration, cognitive function, BBB permeability and neuroinflammatory factors in high-fat diet-induced obese rats. Int J Obes (Lond) 2017; 41(4):639-44.
16. Nameni G, Hajiluian G, Shahabi P, Farhangi MA, Mesgari-Abbasi M, Hemmati MR. The impact of vitamin D supplementation on neurodegeneration, TNF-α concentration in hypothalamus, and CSF-to-plasma ratio of insulin in high-fat-diet-induced obese rats. J Mol Neurosci 2016; 61(2):247-55.
17. Nameni G, Farhangi MA, Hajilouian G, Shahabi P, Mesgari-Abbasi M. Insulin deficiency: A possible link between obesity and cognitive function. Int J Dev Neurosci 2017; 59(15-20).
18. Liang W, L. Menke A, Driessen A, H. Koek G, H. et al. Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology. PLOS ONE 2014; 9(12):e115922.
19. Shojaei Zarghani S, Soraya H, Zarei L, Alizadeh M. Comparison of Three Different Diet-Induced Non Alcoholic Fatty Liver Disease Protocols in Rats: A Pilot Study. Pharmaceutical Sciences 2016; 22(9-15).
20. Abdelkader NA, Sabry D, Al-Ghussein MAS, Dabbous HM, Allam E. Correlation between vitamin D receptor and monocyte chemotactic protein-1 polymorphisms and spontaneous bacterial peritonitis in decompensated liver disease. JGHR 2015; 4(10):1815-20.
21. Wang YC, Hsieh CC, Kuo HF, Tsai MK, Yang SN, Kuo CH, et al. Effect of vitamin D3 on monocyte chemoattractant protein 1 production in monocytes and macrophages. Acta Cardiol Sin 2014; 30(2):144-50.
22. Ning C, Liu N, Lv Y G, Yang, Zhang Y, Yu R, et al. Lipid metabolism and inflammation modulated by Vitamin D in liver of diabetic rats. Lipids Health Dis 2015; 14:31
23. He G, Karin M. NF-κB and STAT3 – key players in liver inflammation and cancer. Cell Res 2011; 21(1):159–68.
24. Sun B, Karin M. NF-κB signaling, liver disease, and hepatoprotective agents. Oncogene 2008; 27(48):6228–44.
25. Beilfuss A, Sowa JP, Sydor S, Beste M, Bechmann LP, Schlattjan M, et al. Vitamin D counteracts fibrogenic TGF-β signaling in human hepatic stellate cells both receptor-dependently and independently. Gut 2015; 64(5):791-9.
26. Chen J, Katz LH, Muñoz NM, Gu S, Shin J, Jogunoori WS, et al. Vitamin D deficiency promotes liver tumor growth in transforming growth factor-β/Smad3-deficient mice through Wnt and Toll-like receptor 7 pathway modulation. Sci Rep 2016; 6:30217.
27. Nobili V, Giorgio V, Liccardo D, Bedogni G, Morino G, Alisi A, et al. Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease. Eur J Endocrinol 2014; 170(4):547-53.
28. Lucaci C, Acalovschi M. The importance of vitamin D status in liver histological progression and response to antiviral therapy. HVM Bioflux 2015; 7(3):140-3.
29. Farhangi MA, Keshavarz SA, Eshraghian M, Ostadrahimi A, Saboor-Yaraghi AA. White blood cell count in women: relation to inflammatory biomarkers, hematological profiles, visceral adiposity, and other cardiovascular risk factors. J Health Popul Nutr 2013; 31(1):58-64.
30. Buettner R, Schölmerich J, Bollheimer LC. High‐fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity 2007; 15(4):798-808.
31. McGill AT, Stewart JM, Lithander FE, Strik CM, Poppitt SD. Relationships of low serum vitamin D 3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutr J 2008; 7(1):4.
32. Asemi Z, Hashemi T, Karamali M, Samimi M, Esmaillzadeh A. Effects of vitamin D supplementation on glucose metabolism, lipid concentrations, inflammation, and oxidative stress in gestational diabetes: a double-blind randomized controlled clinical trial. Am J Clinical Nutr 2013; 98(6):1425-32.