Vitamin D 1,25-Dihydroxyvitamin D Reduces Lipid Accumulation in Hepatocytes by Inhibiting M1 Macrophage Polarization

Overview

Journal World J Gastrointest Oncol

Publisher Baishideng Publishing Group

Date 2024 Dec 16

PMID 39678811

Authors

Wen-Jing Luo

Xian-Wen Dong

Hua Ye

Qiao-Su Zhao

Qiu-Bo Zhang

Wen-Ying Guo

Hui-Wei Liu

Feng Xu

Affiliations

Soon will be listed here.

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD), which is a significant liver condition associated with metabolic syndrome, is the leading cause of liver diseases globally and its prevalence is on the rise in most nations. The protective impact of vitamin D on NAFLD and its specific mechanism remains unclear.

Aim: To examine the role of vitamin D in NAFLD and how vitamin D affects the polarization of hepatic macrophages in NAFLD through the vitamin D receptor (VDR)-peroxisome proliferator activated receptor (PPAR)γ pathway.

Methods: Wild-type C57BL/6 mice were provided with a high-fat diet to trigger NAFLD model and administered 1,25-dihydroxy-vitamin D [1,25(OH)D] supplementation. 1,25(OH)D was given to RAW264.7 macrophages that had been treated with lipid, and a co-culture with AML12 hepatocytes was set up. Lipid accumulation, lipid metabolism enzymes, M1/M2 phenotype markers, proinflammatory cytokines and VDR-PPARγ pathway were determined.

Results: Supplementation with 1,25(OH)D relieved hepatic steatosis and decreased the proinflammatory M1 polarization of hepatic macrophages in NAFLD. Administration of 1,25(OH)D suppressed the proinflammatory M1 polarization of macrophages induced by fatty acids, thereby directly relieving lipid accumulation and metabolism in hepatocytes. The VDR-PPARγ pathway had a notable impact on reversing lipid-induced proinflammatory M1 polarization of macrophages regulated by the administration of 1,25(OH)D.

Conclusion: Supplementation with 1,25(OH)D improved hepatic steatosis and lipid metabolism in NAFLD, linked to its capacity to reverse the proinflammatory M1 polarization of hepatic macrophages, partially by regulating the VDR-PPARγ pathway. The involvement of 1,25(OH)D in inhibiting fatty-acid-induced proinflammatory M1 polarization of macrophages played a direct role in relieving lipid accumulation and metabolism in hepatocytes.

Citing Articles

The role of M1/M2 macrophage polarization in the pathogenesis of obesity-related kidney disease and related pathologies.

Dousdampanis P, Aggeletopoulou I, Mouzaki A Front Immunol. 2025; 15:1534823.

PMID: 39867890 PMC: 11758166. DOI: 10.3389/fimmu.2024.1534823.

References

Chinetti G, Fruchart J, Staels B . Peroxisome proliferator-activated receptors: new targets for the pharmacological modulation of macrophage gene expression and function. Curr Opin Lipidol. 2003; 14(5):459-68. DOI: 10.1097/00041433-200310000-00006. View

Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube J . Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes. 2009; 59(2):347-57. PMC: 2809951. DOI: 10.2337/db09-0016. View

Morris D, Singer K, Lumeng C . Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care. 2011; 14(4):341-6. PMC: 4690541. DOI: 10.1097/MCO.0b013e328347970b. View

Sertznig P, Seifert M, Tilgen W, Reichrath J . Peroxisome proliferator-activated receptor (PPAR) and vitamin D receptor (VDR) signaling pathways in melanoma cells: promising new therapeutic targets?. J Steroid Biochem Mol Biol. 2010; 121(1-2):383-6. DOI: 10.1016/j.jsbmb.2010.03.003. View

Luo W, Xu Q, Wang Q, Wu H, Hua J . Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci Rep. 2017; 7:44612. PMC: 5353732. DOI: 10.1038/srep44612. View

Barchetta I, Cimini F, Cavallo M . Vitamin D and Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): An Update. Nutrients. 2020; 12(11). PMC: 7693133. DOI: 10.3390/nu12113302. View

Maina V, Sutti S, Locatelli I, Vidali M, Mombello C, Bozzola C . Bias in macrophage activation pattern influences non-alcoholic steatohepatitis (NASH) in mice. Clin Sci (Lond). 2011; 122(11):545-53. DOI: 10.1042/CS20110366. View

Odegaard J, Ricardo-Gonzalez R, Goforth M, Morel C, Subramanian V, Mukundan L . Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007; 447(7148):1116-20. PMC: 2587297. DOI: 10.1038/nature05894. View

Sica A, Mantovani A . Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012; 122(3):787-95. PMC: 3287223. DOI: 10.1172/JCI59643. View

10.

Panda D, Miao D, Bolivar I, Li J, Huo R, Hendy G . Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem. 2004; 279(16):16754-66. DOI: 10.1074/jbc.M310271200. View

11.

Li X, Liu Y, Zheng Y, Wang P, Zhang Y . The Effect of Vitamin D Supplementation on Glycemic Control in Type 2 Diabetes Patients: A Systematic Review and Meta-Analysis. Nutrients. 2018; 10(3). PMC: 5872793. DOI: 10.3390/nu10030375. View

12.

Powell E, Wong V, Rinella M . Non-alcoholic fatty liver disease. Lancet. 2021; 397(10290):2212-2224. DOI: 10.1016/S0140-6736(20)32511-3. View

13.

Li P, He K, Li J, Liu Z, Gong J . The role of Kupffer cells in hepatic diseases. Mol Immunol. 2017; 85:222-229. DOI: 10.1016/j.molimm.2017.02.018. View

14.

Zhang X, Zhou M, Guo Y, Song Z, Liu B . 1,25-Dihydroxyvitamin D₃ Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPARγ Signaling Pathway. Biomed Res Int. 2015; 2015:157834. PMC: 4417570. DOI: 10.1155/2015/157834. View

15.

Neuschwander-Tetri B . Non-alcoholic fatty liver disease. BMC Med. 2017; 15(1):45. PMC: 5330146. DOI: 10.1186/s12916-017-0806-8. View

16.

Pacifico L, Osborn J, Bonci E, Pierimarchi P, Chiesa C . Association between Vitamin D Levels and Nonalcoholic Fatty Liver Disease: Potential Confounding Variables. Mini Rev Med Chem. 2018; 19(4):310-332. DOI: 10.2174/1389557518666181025153712. View

17.

Bouhlel M, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S . PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007; 6(2):137-43. DOI: 10.1016/j.cmet.2007.06.010. View

18.

Dixon L, Barnes M, Tang H, Pritchard M, Nagy L . Kupffer cells in the liver. Compr Physiol. 2013; 3(2):785-97. PMC: 4748178. DOI: 10.1002/cphy.c120026. View

19.

Sakpal M, Satsangi S, Mehta M, Duseja A, Bhadada S, Das A . Vitamin D supplementation in patients with nonalcoholic fatty liver disease: A randomized controlled trial. JGH Open. 2018; 1(2):62-67. PMC: 6207029. DOI: 10.1002/jgh3.12010. View

20.

Bessone F, Razori M, Roma M . Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci. 2018; 76(1):99-128. PMC: 11105781. DOI: 10.1007/s00018-018-2947-0. View