Saturated Fat-Mediated Upregulation of IL-32 and CCL20 in Hepatocytes Contributes to Higher Expression of These Fibrosis-Driving Molecules in MASLD

被引:5
作者
Schilcher, Katharina [1 ]
Dayoub, Rania [1 ]
Kubitza, Marion [1 ]
Riepl, Jakob [1 ]
Klein, Kathrin [2 ,3 ]
Buechler, Christa [4 ]
Melter, Michael [1 ]
Weiss, Thomas S. [1 ,5 ]
机构
[1] Univ Hosp Regensburg, Childrens Univ Hosp KUNO, D-93053 Regensburg, Germany
[2] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany
[3] Univ Tubingen, D-70376 Stuttgart, Germany
[4] Univ Hosp Regensburg, Dept Internal Med 1, D-93053 Regensburg, Germany
[5] Univ Hosp Regensburg, Ctr Liver Cell Res, D-93053 Regensburg, Germany
关键词
MASLD; NAFLD; MASH; NASH; steatosis; interleukin; 32; chemokine CC ligand 20; oxidative stress; saturated fatty acid; MAPK pathway; LIVER-REGENERATION; PALMITIC ACID; INFLAMMATION; INTERLEUKIN-32; LIPOTOXICITY; ACCUMULATION; RECEPTOR; HYPOXIA; DISEASE; OBESITY;
D O I
10.3390/ijms241713222
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases, ranging from liver steatosis to metabolic dysfunction-associated steatohepatitis (MASH), increasing the risk of developing cirrhosis and hepatocellular carcinoma (HCC). Fibrosis within MASLD is critical for disease development; therefore, the identification of fibrosis-driving factors is indispensable. We analyzed the expression of interleukin 32 (IL-32) and chemokine CC ligand 20 (CCL20), which are known to be linked with inflammation and fibrosis, and for their expression in MASLD and hepatoma cells. RT-PCR, ELISA and Western blotting analyses were performed in both human liver samples and an in vitro steatosis model. IL-32 and CCL20 mRNA expression was increased in tissues of patients with NASH compared to normal liver tissue. Stratification for patatin-like phospholipase domain-containing protein 3 (PNPLA3) status revealed significance for IL-32 only in patients with I148M (rs738409, CG/GG) carrier status. Furthermore, a positive correlation was observed between IL-32 expression and steatosis grade, and between IL-32 as well as CCL20 expression and fibrosis grade. Treatment with the saturated fatty acid palmitic acid (PA) induced mRNA and protein expression of IL-32 and CCL20 in hepatoma cells. This induction was mitigated by the substitution of PA with monounsaturated oleic acid (OA), suggesting the involvement of oxidative stress. Consequently, analysis of stress-induced signaling pathways showed the activation of Erk1/2 and p38 MAPK, which led to an enhanced expression of IL-32 and CCL20. In conclusion, cellular stress in liver epithelial cells induced by PA enhances the expression of IL-32 and CCL20, both known to trigger inflammation and fibrosis.
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页数:12
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