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The role of sphingosine kinase 2 in alcoholic liver disease.

ABSTRACT: 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?, F4/80, Il-1?). 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.

SUBMITTER: Kwong EK

PROVIDER: S-EPMC6682426 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The role of sphingosine kinase 2 in alcoholic liver disease.

Kwong Eric K EK Liu Runping R Zhao Derrick D Li Xiaojiaoyang X Zhu Weiwei W Wang Xuan X Gurley Emily C EC Lai Guanhua G Liu Jimin J Hylemon Phillip B PB Zhou Huiping H

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 20190416 8

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<sup>-/-</sup>) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 ...[more]

PMID: 31003959

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Project description:Hepatic macrophages (MΦs) are important in the development and progression of alcoholic liver disease (ALD). This study investigates the role of gp91phox (nicotinamide adenine dinucleotide phosphate oxidase 2) in the severity of ALD and specifically in regulating hepatic MΦ efferocytic capability and the subsequent reprogramming associated with resolution of inflammation. After 4 weeks of ethanol feeding, more severe ALD developed in gp91phox-/- mice than in wild-type (WT) C57Bl/6J mice, evidenced by increased liver injury and inflammation. This phenomenon was not sex dependent, and thus the majority of experiments were performed with female mice. While total hepatic MΦ numbers did not differ between genotypes, hepatic infiltrating MΦs (IMs) were slightly more numerous in gp91phox-/- mice, and both IMs and resident Kupffer cells displayed enhanced proinflammatory and reduced tissue-restorative programming compared with these cells from WT mice. The ratio of proinflammatory IMs with higher expression of Ly6C (Ly6Chi) to anti-inflammatory IMs with lower expression of Ly6C (Ly6Clow) was significantly higher in gp91phox-/- mice compared to WT mice. Greater numbers of apoptotic cells accumulated in the liver of gp91phox-/- mice compared to WT mice, and receptors for binding and engulfing apoptotic cells were expressed at much lower levels on both Kupffer cells and IMs of gp91phox-/- mice. Interactions with apoptotic cells (binding and engulfment) in vitro were significantly fewer for gp91phox-/- MΦs than for WT MΦs, resulting in diminished expression of tissue restorative mediators by hepatic MΦs of gp91phox-/- mice. Conclusion: gp91phox plays a critical role in the differentiation of proinflammatory hepatic MΦs to a tissue-restorative phenotype, likely through programming for efferocytosis, and thereby lessens the severity of ALD. These findings enhance our understanding of the tissue environmental cues that regulate MΦ phenotypes. This knowledge could help in designing MΦ-targeting strategies to prevent and treat ALD. (Hepatology Communications 2017;1:765-779).

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The role of sphingosine kinase 2 in alcoholic liver disease.

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The role of sphingosine kinase 2 in alcoholic liver disease.

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