期刊
DIGESTIVE AND LIVER DISEASE
卷 51, 期 8, 页码 1154-1163出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.dld.2019.03.020
关键词
Gut-Liver axis; Hepatic steatosis; Inflammation; Sphingosine 1-phosphate
资金
- National Institutes of Health [R01 DK104893, R01DK-057543]
- VA Merit Award [I01BX004033, 1I01BX001390]
- Research Career Scientist Award [IK6BX004477]
- Massey Cancer Center research fund
Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide. However, the exact mechanisms underlying ALD remain unclear. Previous studies reported that sphingosine kinase 2 (SphK2) plays an essential role in regulating hepatic lipid metabolism. In the current study, we demonstrate that compared to wild-type (WT) mice, SphK2 deficient (SphK2(-/-)) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 days. This is accompanied by a down-regulation of steroid 7-alpha-hydroxylase (Cyp7b1) and an up-regulation of pro-inflammatory mediators (Tnf alpha, F4/80, Il-1 beta). In vitro experiments showed that alcohol induced SphK2 expression in mouse primary hepatocytes and cultured mouse macrophages. Furthermore, alcohol feeding induced a more severe intestinal barrier dysfunction in SphK2(-/-) mice than WT mice. Deficiency of SphK2 impaired the growth of intestinal organoids. Finally, SphK2 expression levels were down-regulated in the livers of human patients with alcoholic cirrhosis and hepatocellular carcinoma compared to healthy controls. In summary, these findings suggest that SphK2 is a crucial regulator of hepatic lipid metabolism and that modulating the SphK2-mediated signaling pathway may represent a novel therapeutic strategy for the treatment of ALD and other metabolic liver diseases. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
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